TW201141489A - Organic compositions to treat Beta-ENaC-related diseases - Google Patents

Organic compositions to treat Beta-ENaC-related diseases Download PDF

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TW201141489A
TW201141489A TW100114186A TW100114186A TW201141489A TW 201141489 A TW201141489 A TW 201141489A TW 100114186 A TW100114186 A TW 100114186A TW 100114186 A TW100114186 A TW 100114186A TW 201141489 A TW201141489 A TW 201141489A
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Taiwan
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antisense strand
rnai agent
enac
antisense
strand
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TW100114186A
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Chinese (zh)
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TWI434692B (en
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Fougerolles Antonin De
John L Diener
Emma Hickman
Gregory Hinkle
Stuart Milstein
Anne-Marie Pulichino
Andrew Sprague
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Novartis Ag
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Abstract

The present disclosure relates to RNAi agents useful in methods of treating Beta-ENaC-related diseases such as cystic fibrosis, pseudohypoaldosteronism type 1 (PHA1), Liddle's syndrome, hypertension, alkalosis, hypokalemia, and obesity-associated hypertension, using a therapeutically effective amount of a RNAi agent to Beta-ENaC.

Description

201141489 六、發明說明： 本申清案根據35 IJ.S.C. § li9(a)-(d)規定主張2010年4月 7曰申β月之美國臨時申請案61/327,379及2〇1〇年5月u曰申 月之美國匕時申請案61/333,398的權利，其内容以全文引 用的方式併入本文中。 【先前技術】 % ^與身體之間的黏膜表面具有許多保護機制。一種防 $形式為以液體清潔表面。液體之量反映上皮液體分泌 (其通常反映與水及陽離子相對離子偶合之陰離子分泌）與 液體吸收（其通常反映與水及相對陰離子偶合之Na+吸收） 之間的平衡。s午多黏膜表面疾病由液體過少引起，此液體 過少又由分泌（過少）與吸收（過多）之間的失衡引起。一種 平衡液體層之方法為降低Na+通道介導之液體吸收。 非電壓閘控阿米洛利（amil〇ride)敏感性納通道在許多器 吕中控制流體及電解質傳輸通過上皮細胞。許多密集的上 皮細胞之頂膜含有鈉通道，其主要特徵在於其對利尿阻斷 劑阿米洛利之高親和力。此等通道介導保持身體鹽與水内 穩定所必需之活性鈉再吸收的第一步。在脊椎動物中，該 等通道控制鈉於腎、結腸、肺及汗腺中之再吸收；其亦在 味知覺中起作用。201141489 VI. INSTRUCTIONS: This application is based on 35 IJ.SC § li9(a)-(d). It claims the US provisional application for April 7th, 2010, and the US provisional application for 61/327,379 and 2〇1 The benefit of U.S. Patent Application Serial No. 61/333,398, the entire disclosure of which is incorporated herein by reference. [Prior Art] There are many protective mechanisms on the mucosal surface between the body and the body. One form of protection is to clean the surface with a liquid. The amount of liquid reflects the balance between epithelial fluid secretion (which typically reflects anion secretion that is ionically coupled to water and cations) and liquid uptake (which typically reflects Na+ absorption coupled with water and relative anions). In the afternoon, many mucosal surface diseases are caused by too little liquid, and this liquid is too small and caused by the imbalance between secretion (too little) and absorption (too much). One method of balancing the liquid layer is to reduce Na+ channel mediated liquid uptake. Non-voltage-gated amil〇ride-sensitive nanochannels control the transport of fluids and electrolytes through epithelial cells in many devices. The apical membrane of many dense epithelial cells contains sodium channels, which are mainly characterized by their high affinity for the diuretic blocker amiloride. These channels mediate the first step in re-absorption of active sodium necessary to maintain body salt and water stability. In vertebrates, these channels control the reabsorption of sodium in the kidneys, colon, lungs, and sweat glands; they also play a role in taste perception.

Na+及液體吸收之限速步驟由上皮鈉（Na+)通道（ENaC)介 導。此等鈉通道為由3個子單元組成之異質複合物：α_ ENaC、β-ENaC及 γ-ENaC。 3-ENaC(亦稱為SCNN1B)編碼此鈉通道之β子單元，且此 154740.doc 201141489 基因之突變及/或改變之表現與若干疾病有關（及/或與疾病 之治療有關）：包括囊腫性纖維化、丨型假醛固酮過少症 (PHA1)、李德爾症候群（Liddleis syndrome)、高血壓、驗 中毒、低鉀血症及肥胖相關之高血壓。 需要與β-ENaC相關疾病有關的治療。 【發明内容】 本發明涵蓋針對β-ENaC之RNAi劑，其適用於治療p_ ENaC相關疾病，諸如囊腫性纖維化、1型假醛固酮過少症 (PHA1)、李德爾症候群、高血壓、鹼中毒、低鉀血症及肥 胖相關之高血壓。本發明亦涵蓋治療患有至少部分由α_ ENaC表現介導之病理學狀態的人類個體之方法，該方法 包含向個體投與治療有效量之RNAi劑β-ENaC的步驟。 本發明提供適用於降低個體（例如哺乳動物，諸如人類） 之β-ENaC含量的特異性RNAi劑及方法。本發明特定提供 雙股RNAi劑，其包含β-ENaC之至少15個或15個以上連續 (contiguous)核苷酸。詳言之，本發明提供包含有〇、1、2 或3個核苷酸與例如表1中提供之RNAi劑之彼等不同的j 5 或1 5個以上連續核苷酸之序列的試劑。在一實施例中， RNAi劑尤其可包含每股少於30個核苷酸，例如1 8_23個核 苷酸、及/或19·21個核苷酸，及/或諸如在例如表1中提供 之彼等。 雙股RNAi劑可具有來自3’及/或5'端之一者或兩者的i、 2、3或4個核苷酸（亦即1-4個nt)之鈍端或懸垂物。雙股 RNAi劑亦可視情況包含1或2個3’帽端及/或一或多個經修 154740.doc 201141489 飾核苦酸。本文提供之序列的經修飾變異體包括其他方面 相同但含有之天然存在核苷酸取代為相應經修飾核苦酸的 彼等。The rate-limiting step for Na+ and liquid uptake is mediated by the epithelial sodium (Na+) channel (ENaC). These sodium channels are heterogeneous complexes composed of 3 subunits: α_ENaC, β-ENaC and γ-ENaC. 3-ENaC (also known as SCNN1B) encodes a beta subunit of this sodium channel, and the mutation and/or alteration of the 154740.doc 201141489 gene is associated with several diseases (and/or with the treatment of the disease): including cysts Sexual fibrosis, sputum pseudoaldosteronism (PHA1), Liddleis syndrome, hypertension, test poisoning, hypokalemia, and obesity-related hypertension. There is a need for treatment related to β-ENaC related diseases. SUMMARY OF THE INVENTION The present invention encompasses RNAi agents against β-ENaC, which are useful for the treatment of p_ENaC-related diseases, such as cystic fibrosis, type 1 pseudoaldosterone (PHA1), lider syndrome, hypertension, alkalosis, Hypokalemia and obesity-related hypertension. The invention also encompasses a method of treating a human subject having a pathological condition mediated at least in part by the expression of a_ENaC, the method comprising the step of administering to the individual a therapeutically effective amount of the RNAi agent β-ENaC. The present invention provides specific RNAi agents and methods suitable for reducing the beta-ENaC content of an individual, such as a mammal, such as a human. The invention specifically provides a double-stranded RNAi agent comprising at least 15 or more than 15 contiguous nucleotides of β-ENaC. In particular, the invention provides reagents comprising a sequence of j 5 or more than 15 contiguous nucleotides having 〇, 1, 2 or 3 nucleotides different from, for example, the RNAi agents provided in Table 1. In one embodiment, the RNAi agent may comprise, inter alia, less than 30 nucleotides per share, such as 18-23 nucleotides, and/or 19.21 nucleotides, and/or such as provided in Table 1, for example. They are the same. A double-stranded RNAi agent can have a blunt end or overhang of i, 2, 3 or 4 nucleotides (i.e., 1-4 nt) from one of the 3' and/or 5' ends or both. The double-stranded RNAi agent may also optionally contain 1 or 2 3' cap ends and/or one or more repaired 154740.doc 201141489 nucleus picric acid. Modified variants of the sequences provided herein include those which are otherwise identical but contain naturally occurring nucleotide substitutions to the corresponding modified nucleotides.

此外’ RNAi劑可僅含有天然存在之核糖核苦酸子單 元’或對一或多個置換核苷酸子單元之糖、磷酸酯或驗基 的一或多個修飾，不管其是否包含核糖核苷酸子單元或去 氧核糖核苷酸子單元。在一實施例中，所揭示RNAi劑之 經修飾變異體包括具有相同序列但具有對一或多個核苷酸 子單元之糖、磷酸g旨或驗基中一或多者的一或多個修飾之 1〇^八丨劑。在一實施例中，修飾改良RNAi劑之功效、穩定 性及/或降低RNAi劑之免疫原性。本發明之一態樣係關於 包含至少一個非天然核苷鹼基之雙股寡核苷酸。在某些實 施例中，非天然核苷鹼基為二氟甲笨基、硝基吲哚基、硝 基。比咯基或硝基咪唑基❶在一特定實施例中，非天然核苷 鹼基為二氟甲苯基。在特定實施例中，兩個寡核苷酸股中 僅一者含有非天然核苷鹼基。在特定實施例中，兩個寡核 苷酸股中兩者皆含有非天然核苷鹼基。 RNAi劑可視情況連接於經選擇以改良一或多種特徵之 配位體，特徵諸如試劑（例如膽固醇或其衍生物）之穩定 性、分佈及/或細胞攝取。RNAi劑可經分離或為用於本文 所述方法之醫藥組合物之—部分。特^言之，醫藥組合物 可經調配以傳遞至肺或鼻孔或調配用於非經腸投與 (parental adininistration)。醫藥組合物可視情況包含兩種 或兩種以上RNAi劑，其每一者皆針對卜ENaC 之相 154740.doc 201141489 同或不同區段。醫藥組合物可視情況另外包含任何p_ENaC 相關疾病之任何已知治療或與其結合使用。 本發明另外提供降低細胞中P_ENac mRNA之含量的方 法，尤其在以ENaC之過度表現或高活性為特徵之疾病的 情形中。本發明亦涵蓋治療患有至少部分由p_ENaC表現介 導之病理學狀態的人類個體之方法，該方法包含向個體投 與治療有效量之RNAi劑β-ENaC的步驟。該等方法包含如 下文進一步描述向個體投與本發明之一種RNAi劑的步 驟。本發明方法利用RNA干擾中涉及之細胞機制以使細胞 中之目標RNA選擇性降級，且包含使細胞與本發明之一種 RNAi劑接觸的步驟。該等方法可對細胞直接進行或可藉 由向哺乳動物個體投與一種本發明RNAi劑/醫藥組合物對 該個體進行。降低細胞中之目標p_ENaC RNA導致降低所 產生的編碼β-ENaC蛋白質之量。在一生物體中，此可導致 降低上皮位差、平衡液體吸收及提高黏膜纖毛清除率。 本發明方法及組合物（例如方法及p_ENaC RNAi劑組合 物）可與本文所述之任何劑量及/或調配物，以及本文所述 之任何投與途徑一起使用。 在隨附圖式及以下說明書中闡述本發明之一或多個實施 例之細節。本發明之其他特徵、目標及優勢自本說明書、 圖式及申請專利範圍將顯而易知。 【實施方式】 本發明涵蓋針對β-ENaC之RNAi劑，其適用於治療β_ ENaC相關疾病（例如與β-ENaC之表現、含量及/或活性突 154740.doc 201141489 變及/或改變有關之疾病、及/或可藉由調節β-ENaC之表 現、含量及/或活性治療之疾病）’諸如囊腫性纖維化、1型 假酸固鋼過少症（PHA1)、李德爾症候群、高血壓、驗中 毒、低鉀血症及肥胖相關之高血壓。本發明亦提供治療患 有至少部分由β-ENaC表現介導之病理學狀態的人類個體之 方法，該方法包含向個體投與治療有效量之RNAi劑β-ENaC的步驟。 本發明之多個實施例包括： 包含本文所述之反義股的RNAi劑。 在一實施例中，本發明係關於包含RNAi劑之組合物， 該RNAi劑包含有義股及反義股’其中該反義股包含有〇、 1、2或3個核苷酸與對例如表1中提供之p_ENac(或對β· EnaC具有特異性之重疊RNAi劑的任何組）具有特異性之 RNAi劑之反義股不同的至少15個連續核苷酸。在另一實 施例中’本發明係關於包含RNAi劑之組合物，該RNAi劑 包含有義股及反義股，其中反義股包含有〇、1、2或3個核 苷酸與本文提供之任何序列的RNAi劑之反義股不同的至 少1 5個連續核苷酸。在另一實施例中，本發明係關於包含 RNAi劑之組合物，該RNAi劑包含第一股及第二股，其中 第一股包含有0' 1、2或3個核苷酸與本文提供之任何 RNAi劑的第一股序列不同之至少丨5個連續核苷酸，且第 二股包含有0、1、2或3個核苷酸與其第二股序列不同之至 少15個連續核苷酸。Furthermore, 'RNAi agents may contain only naturally occurring ribonucleotide subunits' or one or more modifications to the sugar, phosphate or test group of one or more replacement nucleotide subunits, whether or not they contain a ribonucleoside A glycosidic acid unit or a deoxyribonucleotide subunit. In one embodiment, a modified variant of a disclosed RNAi agent comprises one or more of one or more of the sugars, phosphates, or assays having the same sequence but having one or more nucleotide subunits. Modified 1 〇 ^ gossip. In one embodiment, the modification improves the efficacy, stability, and/or reduces the immunogenicity of the RNAi agent. One aspect of the invention pertains to a double-stranded oligonucleotide comprising at least one non-natural nucleobase. In certain embodiments, the non-natural nucleobase is difluoromethyl, nitroguanidino, nitro. In a particular embodiment, the non-natural nucleoside base is a difluorotolyl group. In a particular embodiment, only one of the two oligonucleotide strands contains a non-natural nucleobase. In a particular embodiment, both of the two oligonucleotide strands contain a non-natural nucleobase. The RNAi agent can optionally be linked to a ligand selected to modify one or more characteristics, such as stability, distribution and/or cellular uptake of a reagent such as cholesterol or a derivative thereof. The RNAi agent can be isolated or part of a pharmaceutical composition for use in the methods described herein. In particular, the pharmaceutical composition can be formulated for delivery to the lungs or nostrils or for parental adininistration. The pharmaceutical composition may optionally comprise two or more RNAi agents, each of which is directed to the same or different segments of the phase 154740.doc 201141489 of ENaC. The pharmaceutical composition may optionally comprise or be used in combination with any known treatment of any p_ENaC related disease. The present invention further provides a method of reducing the amount of P_ENac mRNA in a cell, particularly in the case of a disease characterized by overexpression or high activity of ENaC. The invention also encompasses a method of treating a human subject having a pathological condition mediated at least in part by the expression of p_ENaC, the method comprising the step of administering to the individual a therapeutically effective amount of the RNAi agent β-ENaC. Such methods comprise the step of administering to a subject an RNAi agent of the invention as described further below. The method of the invention utilizes the cellular machinery involved in RNA interference to selectively degrade the target RNA in the cell and comprises the step of contacting the cell with a RNAi agent of the invention. Such methods can be carried out directly on the cells or can be carried out by administering to the mammalian individual a RNAi agent/pharmaceutical composition of the invention. Decreasing the target p_ENaC RNA in the cells results in a decrease in the amount of the encoded β-ENaC protein produced. In an organism, this can result in reduced epithelial dislocation, balanced fluid absorption, and increased mucociliary clearance. The methods and compositions of the invention (e. g., methods and p_ENaC RNAi agent compositions) can be used with any of the dosages and/or formulations described herein, as well as any of the routes of administration described herein. The details of one or more embodiments of the invention are set forth in the claims Other features, objects, and advantages of the present invention will be apparent from the description and appended claims. [Embodiment] The present invention encompasses a RNAi agent against β-ENaC, which is suitable for the treatment of a β_ENaC-related disease (for example, a disease associated with the expression, content and/or activity of β-ENaC and/or activity of 154740.doc 201141489) And/or diseases that can be treated by regulating the performance, content and/or activity of β-ENaC) such as cystic fibrosis, type 1 pseudo-acidic hypercoagulopathy (PHA1), lider syndrome, hypertension, test Poisoning, hypokalemia and obesity-related hypertension. The invention also provides a method of treating a human subject suffering from a pathological condition mediated at least in part by the expression of β-ENaC, the method comprising the step of administering to the individual a therapeutically effective amount of the RNAi agent β-ENaC. Various embodiments of the invention comprise: a RNAi agent comprising an antisense strand as described herein. In one embodiment, the invention relates to a composition comprising an RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides and pairs, for example The p_ENac (or any group of overlapping RNAi agents specific for β·EnaC) provided in Table 1 has at least 15 contiguous nucleotides different from the antisense strand of the specific RNAi agent. In another embodiment, the invention relates to a composition comprising an RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides and is provided herein The antisense strand of any sequence of RNAi agents differs by at least 15 contiguous nucleotides. In another embodiment, the invention relates to a composition comprising a RNAi agent comprising a first strand and a second strand, wherein the first strand comprises 0' 1, 2 or 3 nucleotides and is provided herein The first strand of any RNAi agent differs by at least 5 contiguous nucleotides, and the second strand comprises at least 15 contiguous nucleosides having 0, 1, 2 or 3 nucleotides different from its second strand sequence acid.

特定雙鏈體包括以下，其中各雙鏈體包含一組SEq ID 154740.doc 201141489 NO，其中第一 SEQ ID NO對應於第一股（例如有義股），且 第二SEQ ID NO對應於第二股（例如反義股）：AD· 20805(SEQ ID NO. 111 及 112) ; AD-20806(SEQ ID NO. 113 及 114) ; AD-20807(SEQ ID NO. 115 及 116) ; AD- 20808(SEQ ID NO. 117及 118) ; AD-20809(SEQ ID NO. 119 及 120) ； AD-20810(SEQ ID NO. 121 及 122) ； AD-Specific duplexes include the following, wherein each duplex comprises a set of SEq ID 154740.doc 201141489 NO, wherein the first SEQ ID NO corresponds to the first strand (eg, the sense strand) and the second SEQ ID NO corresponds to the Two strands (eg antisense strands): AD 20805 (SEQ ID NO. 111 and 112); AD-20806 (SEQ ID NO. 113 and 114); AD-20807 (SEQ ID NO. 115 and 116); AD- 20808 (SEQ ID NO. 117 and 118); AD-20809 (SEQ ID NO. 119 and 120); AD-20810 (SEQ ID NO. 121 and 122); AD-

20811(SEQ ID NO. 123及 124) ; AD-20812(SEQ ID NO. 125 及 126) ； AD-20813(SEQ ID NO. 127 及 128) ； AD- 20814(SEQ ID NO. 129及 130) ; AD-20815(SEQ ID NO· 131 及 132) ； AD-20816(SEQ ID NO. 133 及 134) ; AD- 20817(SEQ ID NO. 135及 136) ; AD-20818(SEQ ID NO. 137 及 138) ; AD-20819(SEQ ID NO. 139 及 140) ; AD- 20820(SEQ ID NO. 141 及 142) ; AD-20821(SEQ ID NO. 143 及 144) ; AD-20822(SEQ ID NO. 145 及 146) ; AD-20811 (SEQ ID NO. 123 and 124); AD-20812 (SEQ ID NO. 125 and 126); AD-20813 (SEQ ID NO. 127 and 128); AD-20814 (SEQ ID NO. 129 and 130); AD-20815 (SEQ ID NO. 131 and 132); AD-20816 (SEQ ID NO. 133 and 134); AD-20817 (SEQ ID NO. 135 and 136); AD-20818 (SEQ ID NO. 137 and 138) AD-20819 (SEQ ID NO. 139 and 140); AD-20820 (SEQ ID NO. 141 and 142); AD-20821 (SEQ ID NO. 143 and 144); AD-20822 (SEQ ID NO. 145) And 146) ; AD-

20823(SEQ ID NO. 147及 148) ; AD-20824(SEQ ID NO. 149 及 150) ； AD-20825(SEQ ID NO. 151 及 152) ； AD- 20826(SEQ ID NO· 153及 154) ; AD-20827(SEQ ID NO. 155 及 156) ; AD-20828(SEQ ID NO. 157 及 158) ; AD- 20829(SEQ ID NO. 159及 160) ; AD-20830(SEQ ID NO. 161 及 162) ; AD-2083 1(SEQ ID NO. 163 及 164) ; AD- 20832(SEQ ID NO. 165及 166) ; AD-20833(SEQ ID NO. 167 及 168) ; AD-20834(SEQ ID NO. 169 及 170) ; AD- 20835(SEQ ID NO. 171 及 172) ; AD-20836(SEQ ID NO. 173 及 174) ； AD-20837(SEQ ID NO. 175 及 176) ; AD- 154740.doc 201141489 20838(SEQ ID NO_ 177及 178) ; AD-20839(SEQ ID NO. 179 及 180) ； AD-20840(SEQ ID NO. 181 及 182) ； AD- 20841(SEQ ID NO. 183及 184) ; AD-20842(SEQ ID NO. 185 及 186) ; AD-20843(SEQ ID NO. 187 及 188) ; AD- 20844(SEQ ID NO. 189及 190) ; D-20845(SEQ ID NO. 191 及 192) ; AD-20846(SEQ ID NO. 193 及 194) ; AD-20823 (SEQ ID NO. 147 and 148); AD-20824 (SEQ ID NO. 149 and 150); AD-20825 (SEQ ID NO. 151 and 152); AD-20826 (SEQ ID NO. 153 and 154); AD-20827 (SEQ ID NO. 155 and 156); AD-20828 (SEQ ID NO. 157 and 158); AD-20829 (SEQ ID NO. 159 and 160); AD-20830 (SEQ ID NO. 161 and 162) AD-2083 1 (SEQ ID NO. 163 and 164); AD-20832 (SEQ ID NO. 165 and 166); AD-20833 (SEQ ID NO. 167 and 168); AD-20834 (SEQ ID NO. 169 and 170); AD-20835 (SEQ ID NO. 171 and 172); AD-20836 (SEQ ID NO. 173 and 174); AD-20837 (SEQ ID NO. 175 and 176); AD-154740.doc 201141489 20838 (SEQ ID NO_177 and 178); AD-20839 (SEQ ID NO. 179 and 180); AD-20840 (SEQ ID NO. 181 and 182); AD-20841 (SEQ ID NO. 183 and 184); AD -20842 (SEQ ID NO. 185 and 186); AD-20843 (SEQ ID NO. 187 and 188); AD-20844 (SEQ ID NO. 189 and 190); D-20845 (SEQ ID NO. 191 and 192) ; AD-20846 (SEQ ID NO. 193 and 194); AD-

20847(SEQ ID NO. 195及 196) ; AD-20848(SEQ ID NO. 197 及 198) ; AD-20849(SEQ ID NO. 199 及 200) ; AD- 20850(SEQ ID NO. 201 及 202) ; AD-20851(SEQ ID NO. 203 及 204) ; AD-20852(SEQ ID NO. 205 及 206) ; AD- 20861(SEQ ID NO. 207及 208) ; AD-20862(SEQ ID NO. 209 及 210) ； AD-20863(SEQ ID NO. 211 及 212) ; AD- 20864(SEQ ID NO. 213及 214) ; AD-20865(SEQ ID NO. 215 及 216) ; AD-20866(SEQ ID NO. 217 及 218) ; &AD-20867(3£卩10 1^0.219及220)，及其經修飾變異體。20847 (SEQ ID NO. 195 and 196); AD-20848 (SEQ ID NO. 197 and 198); AD-20849 (SEQ ID NO. 199 and 200); AD-20580 (SEQ ID NO. 201 and 202); AD-20851 (SEQ ID NO. 203 and 204); AD-20852 (SEQ ID NO. 205 and 206); AD-20861 (SEQ ID NO. 207 and 208); AD-20862 (SEQ ID NO. 209 and 210) AD-20863 (SEQ ID NO. 211 and 212); AD-20864 (SEQ ID NO. 213 and 214); AD-20865 (SEQ ID NO. 215 and 216); AD-20866 (SEQ ID NO. 217) And 218); & AD-20867 (3£卩10 1^0.219 and 220), and modified variants thereof.

一實施例提供特定雙鏈體之經修飾變異體，其中各雙鏈 體包含一組SEQ ID NO，其中第一 SEQ ID NO對應於第一 股（例如有義股），且第二SEQ ID NO對應於第二股（例如反 義股），其選自由以下組成之群：AD-20805(SEQ ID NO. 1 及 2) ; AD-20806(SEQ ID NO. 3 及 4) ; AD-20807(SEQ ID NO. 5及 6) ; AD-20808(SEQ ID NO· 7及 8) ; AD-20809(SEQ ID NO. 9及 10) ; AD-20810(SEQ ID NO. 11 及 12) ; AD-20811(SEQ ID NO. 13及 14) ; AD-20812(SEQ ID NO. 15及 16) ; AD-20813(SEQ ID NO. 17及 18) ; AD-20814(SEQ ID 154740.doc 201141489One embodiment provides a modified variant of a particular duplex, wherein each duplex comprises a set of SEQ ID NOs, wherein the first SEQ ID NO corresponds to the first strand (eg, the sense strand) and the second SEQ ID NO Corresponding to a second strand (eg, an antisense strand) selected from the group consisting of AD-20805 (SEQ ID NO. 1 and 2); AD-20806 (SEQ ID NO. 3 and 4); AD-20807 ( SEQ ID NO. 5 and 6); AD-20808 (SEQ ID NO. 7 and 8); AD-20809 (SEQ ID NO. 9 and 10); AD-20810 (SEQ ID NO. 11 and 12); AD- 20811 (SEQ ID NOS. 13 and 14); AD-20812 (SEQ ID NOS. 15 and 16); AD-20813 (SEQ ID NO. 17 and 18); AD-20814 (SEQ ID 154740.doc 201141489

NO. 19 及 20) ; AD-20815(SEQ ID NO. 21 及 22) ; AD-20816(SEQ ID NO· 23及 24) ; AD-20817(SEQ ID NO. 25及 26) ; AD-20818(SEQ ID NO. 27及 28) ; AD-20819(SEQ ID NO. 29 及 30) ; AD-20820(SEQ ID NO. 31 及 32) ; AD_ 20821(SEQ ID NO. 33及 34) ; AD-20822(SEQ ID NO. 35及 36) ; AD-20823(SEQ ID NO. 37及 38) ; AD-20824(SEQ ID NO. 39 及 40) ； AD-20825(SEQ ID NO. 41 及 42) ; AD-20826(SEQ ID NO. 43 及 44) ; AD-20827(SEQ ID NO. 45 及 46) ; AD-20828(SEQ ID NO. 47及 48) ; AD-20829(SEQ ID NO. 49 及 50) ； AD-20830(SEQ ID NO. 51 及 52) ; AD-NO. 19 and 20); AD-20815 (SEQ ID NO. 21 and 22); AD-20816 (SEQ ID NO. 23 and 24); AD-20817 (SEQ ID NO. 25 and 26); AD-20818 ( SEQ ID NO. 27 and 28); AD-20819 (SEQ ID NO. 29 and 30); AD-20820 (SEQ ID NO. 31 and 32); AD-20821 (SEQ ID NO. 33 and 34); AD-20822 (SEQ ID NO. 35 and 36); AD-20823 (SEQ ID NO. 37 and 38); AD-20824 (SEQ ID NO. 39 and 40); AD-20825 (SEQ ID NO. 41 and 42); AD -20826 (SEQ ID NO. 43 and 44); AD-20827 (SEQ ID NO. 45 and 46); AD-20828 (SEQ ID NO. 47 and 48); AD-20829 (SEQ ID NO. 49 and 50) ; AD-20830 (SEQ ID NO. 51 and 52); AD-

20831(SEQ ID NO. 53及 54) ; AD-20832(SEQ ID NO. 55及 56) ; AD-20833(SEQ ID NO. 57及 58) ; AD-20834(SEQ ID NO. 59 及 60) ； AD-20835(SEQ ID NO. 61 A 62) ； AD-20836(SEQ ID NO. 63及 64) ; AD-20837(SEQ ID NO. 65及 66) ; AD-20838(SEQ ID NO. 67及 68) ; AD-20839(SEQ ID NO. 69 及 70) ; AD-20840(SEQ ID NO. 71 及 72) ; AD-20841(SEQ ID NO. 73及 74) ; AD-20842(SEQ ID NO. 75及 76) ; AD-20843(SEQ ID NO. 77及 78) ; AD-20844(SEQ ID NO. 79 及 80) ； AD-20845(SEQ ID NO. 81 及 82) ; AD-20846(SEQ ID NO. 83及 84) ; AD-20847(SEQ ID NO. 85及 86) ; AD-20848(SEQ ID NO. 87及 88) ; AD-20849(SEQ ID NO. 89 及 90) ; AD-20850(SEQ ID NO. 91 A 92) ； AD-20851(SEQ ID NO. 93及 94) ; AD-20852(SEQ ID NO. 95及 96) ; AD-20861(SEQ ID NO. 97及 98) ; AD-20862(SEQ ID 154740.doc -10- 201141489 NO. 99及 100) ; AD-20863(SEQ ID NO. 101 及 102) ; AD-20864(SEQ ID NO· 103及 104) ; AD-20865(SEQ ID NO. 105 及 106) ; AD-20866(SEQ ID NO. 107 及 108);及 AD-20867(SEQIDNO. 109 及 110)。 特定組合物 在一實施例中，本發明係關於包含具有反義股之RNAi 劑之組合物，其中該反義股包含有0、1、2或3個核苷酸與 本文表（例如表1)中提供之選自任何序列（或重疊序列組）的 β-ENaC之RNAi劑之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含RNAi劑之組合物，該 RNAi劑包含有義股及反義股，其中該反義股包含有〇、 1、2或3個核苷酸與本文表（例如表1)中提供之選自任何序 列（或重疊序列組）的β-ENaC之RNAi劑之反義股不同的至 少15個連續核苷酸。在另一實施例中，本發明係關於包含 RNAi劑之組合物’該RNAi劑包含有義股及反義股，其中 反義股包含有0、1、2或3個核苷酸與本文提供之任何序列 的RNAi劑之反義股不同的至少15個連續核苷酸。在另一 實施例中，本發明係關於包含RNAi劑之組合物，該RNAi 劑包含第一股及第二股，其中第一股包含有〇、1、2或3個 核苷酸與本文提供之任何RNAi劑的第一股序列不同之至 少15個連續核苷酸，且第二股包含有〇、1、2或3個核苷酸 與其第二股序列不同之至少15個連續核苷酸。特定雙鏈體 包括上文&供及如表1中任何一或多者所列之彼等特異性 雙鏈體。上文各組合物之其他經修飾序列（例如包含一或 154740.doc • 11 · 201141489 多個經修飾鹼基之序列）亦作為本發明之一部分而涵蓋。 下表A1提供β-ENaC之多種RNAi劑之有義股及反義股的 未經修飾及實例經修飾序列的SEQ ID NO。每一者之鹼基 組成為表1中更詳細提供之由SEQ ID NO表示之特異性序 列，且其部分提供於表2中。20831 (SEQ ID NOS. 53 and 54); AD-20832 (SEQ ID NOS. 55 and 56); AD-20833 (SEQ ID NOS. 57 and 58); AD-20834 (SEQ ID NO. 59 and 60); AD-20835 (SEQ ID NO. 61 A 62); AD-20836 (SEQ ID NO. 63 and 64); AD-20837 (SEQ ID NO. 65 and 66); AD-20838 (SEQ ID NO. 67 and 68) AD-20839 (SEQ ID NO. 69 and 70); AD-20840 (SEQ ID NO. 71 and 72); AD-20841 (SEQ ID NO. 73 and 74); AD-20842 (SEQ ID NO. 75) And 76); AD-20843 (SEQ ID NO. 77 and 78); AD-20844 (SEQ ID NO. 79 and 80); AD-20845 (SEQ ID NO. 81 and 82); AD-20846 (SEQ ID NO) 83 and 84); AD-20847 (SEQ ID NO. 85 and 86); AD-20848 (SEQ ID NO. 87 and 88); AD-20849 (SEQ ID NO. 89 and 90); AD-20850 (SEQ ID NO. 91 A 92); AD-20851 (SEQ ID NO. 93 and 94); AD-20852 (SEQ ID NO. 95 and 96); AD-20861 (SEQ ID NO. 97 and 98); AD-20862 (SEQ ID 154740.doc -10- 201141489 No. 99 and 100); AD-20863 (SEQ ID NO. 101 and 102); AD-20864 (SEQ ID NO. 103 and 104); AD-20865 (SEQ ID NO) 105 and 106); AD-20866 (SEQ ID NO. 107 and 108); and AD-20867 (SEQ ID NO. 109 and 110). SPECIFIC COMPOSITIONS In one embodiment, the invention relates to a composition comprising an RNAi agent having an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides and a table herein (eg, Table 1) The antisense strand of the RNAi agent of β-ENaC selected from any sequence (or overlapping sequence set) is different from at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising an RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides The antisense strand of the RNAi agent of β-ENaC selected from any sequence (or overlapping sequence set) provided in (for example, Table 1) differs by at least 15 contiguous nucleotides. In another embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides provided herein The antisense strand of any sequence of RNAi agents differs by at least 15 contiguous nucleotides. In another embodiment, the invention relates to a composition comprising a RNAi agent comprising a first strand and a second strand, wherein the first strand comprises 〇, 1, 2 or 3 nucleotides and is provided herein Any of the RNAi agents differ in the first strand sequence by at least 15 contiguous nucleotides, and the second strand comprises at least 15 contiguous nucleotides differing from the second strand sequence by 〇, 1, 2 or 3 nucleotides . Specific duplexes include the above & and their specific duplexes as listed in any one or more of Table 1. Other modified sequences of the above compositions (e.g., sequences comprising one or 154740.doc • 11 · 201141489 multiple modified bases) are also contemplated as part of the present invention. Table A1 below provides SEQ ID NO for unmodified and example modified sequences of the sense and antisense strands of various RNAi agents of β-ENaC. The base composition of each is the specific sequence represented by SEQ ID NO, which is provided in more detail in Table 1, and a part thereof is provided in Table 2.

表A1.針對β-ENaC之RNAi劑的第一及第二股（例如有義 (「SS」）及反義（「AS」）股）之SEQ ID NO RNAi劑-雙鏈體名稱 經修飾序列 SEQ ID NO 未經修飾序列 SEQ ID NO AD-20805 有義 1 111 反義 2 112 AD-20806 有義 3 113 反義 4 114 AD-20807 有義 5 115 反義 6 116 AD-20808 有義 7 117 反義 8 118 AD-20809 有義 9 119 反義 10 120 AD-20810 有義 11 121 反義 12 122 AD-20811 有義 13 123 反義 14 124 AD-20812 有義 15 125 反義 16 126 AD-20813 有義 17 127 反義 18 128 AD-20814 有義 19 129 反義 20 130 AD-20815 有義 21 131 反義 22 132 AD-20816 有義 23 133 反義 24 134 AD-20817 有義 25 135 反義 26 136 AD-20818 有義 27 137 反義 28 138 154740.doc -12- 201141489Table A1. Modified sequence of SEQ ID NO RNAi agent-duplex name for the first and second strands of the RNAi agent for β-ENaC (eg, sense ("SS") and antisense ("AS") shares) SEQ ID NO Unmodified sequence SEQ ID NO AD-20805 Meaning 1 111 Antisense 2 112 AD-20806 Meaning 3 113 Antisense 4 114 AD-20807 Meaning 5 115 Antisense 6 116 AD-20808 Sense 7 117 Antisense 8 118 AD-20809 Sense 9 119 Antisense 10 120 AD-20810 Sense 11 121 Antisense 12 122 AD-20811 Meaning 13 123 Antisense 14 124 AD-20812 Meaning 15 125 Antisense 16 126 AD- 20813 Meaning 17 127 Antisense 18 128 AD-20814 Meaning 19 129 Antisense 20 130 AD-20815 Meaning 21 131 Antisense 22 132 AD-20816 Meaning 23 133 Antisense 24 134 AD-20817 Meaning 25 135义26 136 AD-20818 Sense 27 137 Antisense 28 138 154740.doc -12- 201141489

AD-20819 有義 29 139 反義 30 140 AD-20820 有義 31 141 反義 32 142 AD-20821 有義 33 143 反義 34 144 AD-20822 有義 35 145 反義 36 146 AD-20823 有義 37 147 反義 38 148 AD-20824 有義 39 149 反義 40 150 AD-20825 有義 41 151 反義 42 152 AD-20826 有義 43 153 反義 44 154 AD-20827 有義 45 155 反義 46 156 AD-20828 有義 47 157 反義 48 158 AD-20829 有義 49 159 反義 50 160 AD-20830 有義 51 161 反義 52 162 AD-20831 有義 53 163 反義 54 164 AD-20832 有義 55 165 反義 56 166 AD-20833 有義 57 167 反義 58 168 AD-20834 有義 59 169 反義 60 170 AD-20835 有義 61 171 反義 62 172 AD-20836 有義 63 173 反義 64 174 AD-20837 有義 65 175 反義 66 176 AD-20838 有義 67 177 反義 68 178 AD-20839 有義 69 179 反義 70 180 AD-20840 有義 71 181 反義 72 182 154740.doc -13- 201141489 AD-20841 有義 73 183 反義 74 184 AD-20842 有義 75 185 反義 76 186 AD-20843 有義 77 187 反義 78 188 AD-20844 有義 79 189 反義 80 190 AD-20845 有義 81 191 反義 82 192 AD-20846 有義 83 193 反義 84 194 AD-20847 有義 85 195 反義 86 196 AD-20848 有義 87 197 反義 88 198 AD-20849 有義 89 199 反義 90 200 AD-20850 有義 91 201 反義 92 202 AD-20851 有義 93 203 反義 94 204 AD-20852 有義 95 205 反義 96 206 AD-20861 有義 97 207 反義 98 208 AD-20862 有義 99 209 反義 100 210 AD-20863 有義 101 211 反義 102 212 AD-20864 有義 103 213 反義 104 214 AD-20865 有義 105 215 反義 106 216 AD-20866 有義 107 217 反義 108 218 AD-20867 有義 109 219 反義 110 220AD-20819 Meaning 29 139 Antisense 30 140 AD-20820 Meaning 31 141 Antisense 32 142 AD-20821 Meaning 33 143 Antisense 34 144 AD-20822 Meaning 35 145 Antisense 36 146 AD-20823 Meaning 37 147 antisense 38 148 AD-20824 sense 39 149 antisense 40 150 AD-20825 sense 41 151 antisense 42 152 AD-20826 sense 43 153 antisense 44 154 AD-20827 sense 45 155 antisense 46 156 AD -20828 义义47 157 Antisense 48 158 AD-20829 Sense 49 159 Antisense 50 160 AD-20830 Sense 51 161 Antisense 52 162 AD-20831 Sense 53 163 Antisense 54 164 AD-20832 Sense 55 165 Antisense 56 166 AD-20833 Sense 57 167 Antisense 58 168 AD-20834 Meaning 59 169 Antisense 60 170 AD-20835 Sense 61 171 Antisense 62 172 AD-20836 Sense 63 173 Antisense 64 174 AD- 20837 Sense 65 175 Antisense 66 176 AD-20838 Sense 67 177 Antisense 68 178 AD-20839 Sense 69 179 Antisense 70 180 AD-20840 Sense 71 181 Antisense 72 182 154740.doc -13- 201141489 AD -20841 Righteous 73 183 Antisense 74 184 AD-20842 Righteous 75 185 Antisense 76 186 AD-20843 Righteous 77 187 Antisense 78 188 AD-20844 Righteous 79 189 Antisense 80 190 AD-20845 Righteousness 81 191 Antisense 82 192 AD-20846 Righteousness 83 193 Antisense 84 194 AD-20847 Meaning 85 195 Antisense 86 196 AD-20848 Sense 87 197 Antisense 88 198 AD-20849 Sense 89 199 Antisense 90 200 AD-20850 Sense 91 201 Antisense 92 202 AD-20851 Sense 93 203 Antisense 94 204 AD-20852 Sense 95 205 antisense 96 206 AD-20861 sense 97 207 antisense 98 208 AD-20862 sense 99 209 antisense 100 210 AD-20863 sense 101 211 antisense 102 212 AD-20864 sense 103 213 antisense 104 214 AD -20865 Righteousness 105 215 Antisense 106 216 AD-20866 Meaning 107 217 Antisense 108 218 AD-20867 Meaning 109 219 Antisense 110 220

舉例而言，在表A1中，RNAi劑AD-20805之例示性經修 飾序列由SEQ ID NO: 1(有義股）及SEQ ID NO: 2(反義股） 表示。AD-20805之未經修飾之序列由SEQ ID NO: 111(有 154740.doc •14· 201141489 義股）及SEQ ID NO: 112(反義股）表示。因此，表A1呈現針 對β-ENaC之多種RNAi劑中每一者之未經修飾序列之第一 及第二股的SEQ ID NO識別符及至少—種例示性經修飾序 列。 包含本文所述之反義股的RNAi劑。 在一特定實施例中’本發明係關於包含具有反義股之 RNAi劑之組合物，其中該反義股包含有〇、i、2或3個核 酸與選自本文提供及例如表1列出之特異性雙鏈體中之 彼專反義股的針對β-ENaC之RNAi劑之反義股不同的至少 15個連續核苷酸。 下文描述此實施例之多個具體實施例。 在一實施例中，組合物另外包含針對p_ENaC之第二 RNAi劑。在多個實施例中，第二RNAi劑與第一 RNAi劑物 理上分離，或兩者物理上連接（例如共價連接或結合）。 在一實施例中，反義股長度為約3〇 nt或3〇 nt以下。 在一實施例中’有義股及反義股形成長度約丨5至約3 〇個 核苷酸對之雙鏈體區。 在一實施例中’反義股長度為約15至約36 nt，包括長度 約18至約30 nt，且另外包括長度約19至約23 nt。在一實施 例中’反義股具有至少選自約15 nt、約16 nt、約17 nt、 約 18 nt、約 19 nt、約 20 nt、約 21 nt、約 22 nt、約 23 nt、 約 24 nt、約 25 nt、約 26 nt、約 27 nt、約 28 nt、約 29 nt及 約30 nt之長度。 在一實施例中’ RNAi劑包含使RNAi劑在生物樣品或環 154740.doc 1€ 201141489 境（例如血清或腸灌洗液）中穩定性增加的修飾。 在一實施例中’ RNAi劑包含至少一個糖骨架修飾（例如 硫代填酸醋鍵聯）及/或至少一個2,-經修飾核普酸。在—實 施例中’所有嘧啶為2Ό-曱基-修飾核苷酸。 在一實施例中，RNAi劑包含：至少一個5··尿苷_腺嗓吟_ SO’-uad1)二核苷酸，其中尿苷為2，_經修飾核苷酸；及/或 至少一個5’-尿苷·鳥嘌呤_3，（5i_Ug_3i)二核苷酸，其中5，-尿 苦為2’-經修飾核苷酸；及/或至少一個5，_胞苷·腺嘴吟_ 3·(5·-(^-3’）二核苷酸，其中5，_胞苷為2，_經修飾核苷酸；及/ 或至少一個5’-尿苷-尿苷_3'(5'-uu-3')二核苷酸，其中5，_尿 苦為2'-經修飾核苷酸。 在一實施例中，RNAi劑包含選自由以下組成之群的2，_ 修飾：2’-去氧、2，_去氧_2ι_氟、2，_〇_曱基、2，_〇_甲氧基乙 基（2’-0·Μ0Ε)、2，-〇-胺基丙基（2，_〇·ΑΡ)、二曱胺基 乙基（2’-0-DMA0E)、2，-0-二甲胺基丙基（2，_〇_dmap)、2，_ 〇-—甲胺基乙氧基乙基（2’_〇_DMAEOE)及2'-〇-N-甲基乙醯 胺基（2 -O-NMAh在一實施例中，所有嘧啶為2,〇_曱基_修 飾核苷酸》 在一實施例中’ RNAi劑包含鈍端。 在一實施例中，RNAi劑包含具有1至4個未配對核苷酸 之懸垂物。 在一實施例t ’ RNAi劑在RNAi劑之反義股的3,端包含 懸垂物。 在一實施例中，RNAi劑接合至一或多種診斷化合物、 154740.doc 201141489 報導基團、交聯劑、賦予核酸酶抗性之部分、天然或非尋 常核芽驗基（unusual nucleobase)、親脂性分子、膽固醇、 脂質、植物凝集素（lectin)、類固醇、烏蘇醇（uva〇i)、龍舌 蘭皂苷元（hecigenin)、薯蕷皂苷元（di〇sgenin)、萜類、三 萜、菝窫皂苷元（sarsasapogenin)、無羁萜（Friedeiin)、表 木栓醇衍生之石膽酸、維生素、碳水化合物、聚葡萄糖、 普魯蘭（pullulan)、甲殼素、聚葡萄胺糖、合成碳水化合 物、寡乳酸酯15-聚合體（15-mer)、天然聚合物、低分子量 或中等分子量聚合物、菊糖、環糊精、玻尿酸、蛋白質、 蛋白質結合劑、靶向整合素之分子、聚陽離子、肽、多元 胺、肽模擬物及/或運鐵蛋白。 在一實施例中，RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約6〇%。 在一實施例中’ RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約7〇〇/0。 在一實施例中，RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約80%。 在一實施例中，RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約90%。 在一實施例中，RNAi之EC50不超過約0.1 nM。 在一實施例中，RNAi之EC50不超過約0.01 nM。 在一實施例中，RNAi之EC50不超過約0.001 nM。 包含本文所述第一及第二股之RNAi劑 在一特定具體實施例中，本發明係關於一種包含RNAi 154740.doc •17- 201141489 劑之組合物，該RNAi劑包含第一股及第二股，其中該第 一股及該第二股包含各自有〇、i、2或3個核苷酸分別與針 對選自本文提供及例如表1列出之特異性雙鏈體的β_ΕΝ&(： 之RNAi劑之第一股及第二股不同的至少15個連續核普 酸0 下文描述此實施例之多個具體實施例。 在一實施例中’組合物另外包含針對β—ENaC之第二 RNAi劑。在多個實施你|中，第二RNAi劑與第一RNAi劑物 理上分離，或兩者物理上連接（例如共價連接或結合）。 在一實施例中’反義股長度為約3 0 nt或3 0 nt以下。 在一實施例中，有義股及反義股形成長度約15至約3〇加 對之雙鏈體區。 在一實施例中，反義股長度為約1 5至約36 nt，包括長度 約18至約23 nt，且包括長度約19至約23 nt〇在一實施例 中’反義股具有至少選自約15 nt、約16 nt、約17 M、約 18 nt 、約 19 nt 、約 20 nt 、約 21 nt 、約 22 nt 、約 23 nt 、約 24 nt、約 25 nt、，約 26 nt、，約 27 nt、約 28 nt、約 29 加及約 30 nt之長度。 在一實施例中，RNAi劑包含使尺>^^劑在生物樣品或与 境（例如血清或腸灌洗液）中穩定性增加的修飾。 在-實施例中，RNAi劑包含至少一個糖骨架修飾（例女 疏代磷酸酯鍵聯）及/或至少一個2，·經修飾核普酸。在— 施例中，所有嘧啶為2·0-曱基-修飾核普酸。 在一實施例中，RNAi劑包含：至少一個 個5 ·尿苷-腺嘌呤 I54740.doc -18· 201141489 3\5'-Ua-3')二核苷酸，其中尿苷為2'-經修飾核苦酸；及/或 至少一個5'-尿苷-鳥嘌呤_3，（5，_Ug_3，）二核苷酸，其中5，_尿 芽為2’-經修飾核苷酸；及/或至少一個5，_胞苦-腺嗓吟_ 3'(5’-Ca-3〇二核苷酸，其中5·_胞苷為2’-經修飾核苷酸；及/ 或至少一個5，-尿苷-尿苷_3，(5，-uu-3，）二核苷酸，其中5，_尿 苷為2·-經修飾核苷酸。 在一實施例中，RNAi劑包含選自由以下組成之群的2，_ 修飾：2’-去氧、2’-去氧_2，_氟、2，-0-甲基、2'-0-甲氧基乙 基（2’-〇-ΜΟΕ)、2，-0·胺基丙基（2，-〇-AP)、2，-0-二甲胺基 乙基（2’-〇-DMAOE)、2··0-二甲胺基丙基（2，-〇-DMAP)、2，-〇_二甲胺基乙氧基乙基（2，-〇-DMAEOE)及2，·0-Ν-甲基乙醯 胺基（2·-0-ΝΜΑ)。 在一實施例中’ RNAi劑包含鈍端。 在一實施例中，RNAi劑包含具有及至4個未配對核苷酸 之懸垂物。 在一實施例中，RNAi劑在RNAi劑之反義股的3,端包含 懸垂物。 在一實施例中，RNAi劑接合至一或多種診斷化合物、 報導基團、交聯劑、賦予核酸酶抗性之部分、天然或非尋 常核苦驗基、親脂性分子、 、膽固醇、脂質、植物凝集素、For example, in Table A1, an exemplary modified sequence of the RNAi agent AD-20805 is represented by SEQ ID NO: 1 (sense stock) and SEQ ID NO: 2 (antisense strand). The unmodified sequence of AD-20805 is represented by SEQ ID NO: 111 (with 154740.doc •14·201141489 shares) and SEQ ID NO: 112 (antisense strand). Thus, Table A1 presents the SEQ ID NO identifiers and at least one exemplary modified sequence of the first and second strands of the unmodified sequence for each of the various RNAi agents of β-ENaC. A RNAi agent comprising an antisense strand as described herein. In a particular embodiment, the invention relates to a composition comprising a RNAi agent having an antisense strand, wherein the antisense strand comprises 〇, i, 2 or 3 nucleic acids and is selected from the list and provided in Table 1, for example At least 15 contiguous nucleotides of the antisense strand of the RNAi agent of β-ENaC of the specific antisense strand of the specific duplex. A number of specific embodiments of this embodiment are described below. In one embodiment, the composition further comprises a second RNAi agent for p_ENaC. In various embodiments, the second RNAi agent is physically separated from the first RNAi agent, or both are physically linked (e.g., covalently linked or bound). In one embodiment, the antisense strand is about 3 〇 nt or less. In one embodiment, the sense and antisense strands form a duplex region of from about 5 to about 3 nucleotide pairs in length. In one embodiment, the antisense strand is from about 15 to about 36 nt in length, including from about 18 to about 30 nt in length, and additionally comprises from about 19 to about 23 nt in length. In one embodiment, the antisense strand has at least selected from the group consisting of at least about 15 nt, about 16 nt, about 17 nt, about 18 nt, about 19 nt, about 20 nt, about 21 nt, about 22 nt, about 23 nt, about 24 nt, about 25 nt, about 26 nt, about 27 nt, about 28 nt, about 29 nt, and about 30 nt in length. In one embodiment, the 'RNAi agent comprises a modification that increases the stability of the RNAi agent in a biological sample or loop (e.g., serum or intestinal lavage). In one embodiment, the 'RNAi agent comprises at least one sugar backbone modification (e.g., thiophenate linkage) and/or at least one 2,-modified nucleotide acid. In the examples - all pyrimidines are 2-indolyl-modified nucleotides. In one embodiment, the RNAi agent comprises: at least one 5·. uridine-adenine_SO'-uad1) dinucleotide, wherein the uridine is 2, a modified nucleotide; and/or at least one 5'-uridine-guanine_3, (5i_Ug_3i) dinucleotide, wherein 5, - urinary bitter is 2'-modified nucleotide; and / or at least one 5, _ cytidine · gland sputum _ 3. (5·-(^-3') dinucleotide, wherein 5,-cytidine is 2, a modified nucleotide; and/or at least one 5'-uridine-uridine-3' 5'-uu-3') dinucleotide, wherein 5, _ urinary is 2'-modified nucleotide. In one embodiment, the RNAi agent comprises a 2, _ modification selected from the group consisting of: 2'-deoxygenation, 2,_deoxy-2ι_fluoro, 2,_〇-mercapto, 2,_〇_methoxyethyl (2'-0·Μ0Ε), 2,-〇-amino group Propyl (2, 〇 ΑΡ ΑΡ), diamidoethyl (2'-0-DMA0E), 2,-0-dimethylaminopropyl (2, 〇 d dmap), 2, _ 〇 -Methylaminoethoxyethyl (2'_〇_DMAEOE) and 2'-〇-N-methylacetamidoamine (2-O-NMAh In one embodiment, all pyrimidines are 2, 〇 _Mercapto-modified nucleotides In one embodiment, the 'RNAi agent contains In one embodiment, the RNAi agent comprises a suspension having from 1 to 4 unpaired nucleotides. In one embodiment, the t'RNAi agent comprises a pendant at the 3' end of the antisense strand of the RNAi agent. In one embodiment, the RNAi agent is conjugated to one or more diagnostic compounds, 154740.doc 201141489 reporter group, crosslinker, nuclease resistant portion, natural or unusual nuclear nucleobase, lipophilic Molecules, cholesterol, lipids, lectin, steroids, usu〇i, hecigenin, di〇sgenin, terpenoids, triterpenoids, terpenoids Saponin (sarsasapogenin), sputum (Friedeiin), sulphate-derived lithocholic acid, vitamins, carbohydrates, polydextrose, pullulan, chitin, polyglucosamine, synthetic carbohydrates, Oligolactate 15-polymer (15-mer), natural polymer, low molecular or medium molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein binder, molecule targeting integrins, polycation Peptide, Monoamine, peptidomimetic and/or transferrin. In one embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro at least about 6% in H441 cells at a concentration of 1 〇 nM. In one embodiment, the 'RNAi agent' is capable of inhibiting the expression of the β-ENaC gene in vitro at a concentration of 1 〇 nM in H441 cells by at least about 7 〇〇/0. In one embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 80% in H441 cells at a concentration of 1 〇 nM. In one embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 90% in H441 cells at a concentration of 1 〇 nM. In one embodiment, the RNA50 has an EC50 of no more than about 0.1 nM. In one embodiment, the RNA50 has an EC50 of no more than about 0.01 nM. In one embodiment, the RNAi has an EC50 of no more than about 0.001 nM. RNAi agent comprising the first and second strands described herein In a specific embodiment, the invention relates to a composition comprising RNAi 154740.doc • 17-201141489, the RNAi agent comprising the first and second a strand, wherein the first strand and the second strand comprise respective 〇, i, 2 or 3 nucleotides respectively associated with β_ΕΝ& (for: selected from the specific duplexes provided herein and listed, for example, in Table 1; The first and second strands of the RNAi agent differ from at least 15 consecutive nucleotide acids. A number of specific embodiments of this embodiment are described below. In one embodiment, the composition additionally includes a second for beta-ENaC. RNAi agent. In a plurality of implementations, the second RNAi agent is physically separated from the first RNAi agent, or both are physically linked (eg, covalently linked or bound). In one embodiment, the length of the antisense strand is About 30 nt or less than 30 nt. In one embodiment, the sense strand and the antisense strand form a duplex length of from about 15 to about 3 Å. In one embodiment, the length of the antisense strand is From about 15 to about 36 nt, including from about 18 to about 23 nt in length, and including from about 19 to about 23 nt in length In the embodiment, the antisense strand has at least selected from the group consisting of at least about 15 nt, about 16 nt, about 17 M, about 18 nt, about 19 nt, about 20 nt, about 21 nt, about 22 nt, about 23 nt, about 24 nt. , about 25 nt, about 26 nt, about 27 nt, about 28 nt, about 29 plus, and about 30 nt in length. In one embodiment, the RNAi agent comprises a sizing agent>^ in a biological sample or Modification of increased stability in the context (eg, serum or intestinal lavage). In an embodiment, the RNAi agent comprises at least one sugar backbone modification (eg, female phosphorothioate linkage) and/or at least one Modifying the nucleotide acid. In the embodiment, all pyrimidines are 2·0-mercapto-modified nucleotides. In one embodiment, the RNAi agent comprises: at least one 5 uridine-adenine I54740.doc - 18· 201141489 3\5'-Ua-3') dinucleotide, wherein the uridine is 2'-modified nucleotide acid; and/or at least one 5'-uridine-guanine_3, (5, _Ug_3,) dinucleotide, wherein 5, _ urinary bud is 2'-modified nucleotide; and / or at least one 5, _ sulphate - adenine _ 3 ' (5'-Ca-3 〇 two Nucleotide, wherein 5·- cytidine is 2'-modified nucleotide And/or at least one 5,-uridine-uridine-3, (5,-uu-3,) dinucleotide, wherein 5,_uridine is a 2'-modified nucleotide. In an embodiment Wherein the RNAi agent comprises a 2,_ modification selected from the group consisting of: 2'-deoxygenation, 2'-deoxy-2, fluoro, 2,-0-methyl, 2'-0-methoxy Ethyl (2'-fluorene-fluorene), 2,-0-aminopropyl (2,-fluorene-AP), 2,-0-dimethylaminoethyl (2'-fluorene-DMAOE), 2 ··0-Dimethylaminopropyl (2,-〇-DMAP), 2,-〇-dimethylaminoethoxyethyl (2,-〇-DMAEOE) and 2,·0-Ν-A Ethylamino group (2·-0-ΝΜΑ). In one embodiment the 'RNAi agent comprises a blunt end. In one embodiment, the RNAi agent comprises a suspension having up to 4 unpaired nucleotides. In one embodiment, the RNAi agent comprises a pendant at the 3' end of the antisense strand of the RNAi agent. In one embodiment, the RNAi agent is conjugated to one or more diagnostic compounds, a reporter group, a cross-linking agent, a nuclease-resistant portion, a natural or unusual nuclear test group, a lipophilic molecule, cholesterol, a lipid, Plant lectin,

糖、合成碳水化合物、 糖、普魯蘭、甲殼素、聚葡萄胺 寡乳酸酯15-聚合體、天然聚合 154740.doc -19· 201141489 物、低分子量或中等分子量聚合物、菊糖、環糊精、玻尿 酸、蛋白質、蛋白質結合劑、靶向整合素之分子、聚陽離 子、肽、多元胺、肽模擬物及/或運鐵蛋白。 在一貫施例中，RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約6〇%。 在一實施例中，RNAi劑在H441細胞中在1 〇 濃度下 能夠將β-ENaC基因之表現活體外抑制至少約7〇〇/〇。 在一實施例中，RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約8〇%。 在一貫施例中’ RNAi劑在H441細胞中在1 〇 nM之濃度下 能夠將β-ENaC基因之表現活體外抑制至少約9〇0/〇。 在一實施例中，RNAi之EC50不超過約〇.1 nM。 在一實施例中，RNAi之EC50不超過約〇.〇1 nM。 在一實施例中，RNAi之EC50不超過約o.ooi nM。 使用本文所述RNAi劑之治療方法Sugar, synthetic carbohydrates, sugar, pullulan, chitin, polyglucosamine oligolactone 15-polymer, natural polymerization 154740.doc -19· 201141489, low molecular or medium molecular weight polymer, inulin, ring Dextrin, hyaluronic acid, protein, protein binder, molecules that target integrins, polycations, peptides, polyamines, peptidomimetics, and/or transferrin. In a consistent embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro at least about 6% in H441 cells at a concentration of 1 〇 nM. In one embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro at least 1 〇〇/〇 in H441 cells at a concentration of 1 〇. In one embodiment, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro at least about 8% in H441 cells at a concentration of 1 〇 nM. In a consistent example, the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro at a concentration of 1 〇 nM in H441 cells by at least about 9 〇 0 / 〇. In one embodiment, the EC50 of RNAi does not exceed about 〇1 nM. In one embodiment, the EC50 of RNAi does not exceed about 〇.〇1 nM. In one embodiment, the EC50 of RNAi does not exceed about o.ooi nM. Therapeutic methods using the RNAi agents described herein

在一特定實施例中’本發明係關於治療個體中p_ENaC 相關疾病之方法’包含向個體投與治療有效量之組合物的 步驟’該組合物包含具有至少一反義股之RNAi劑，其中 反義股包含有0、1、2或3個核苷酸與針對選自本文提供及 例如表1所列之特異性雙鏈體之p_ENaC的RNAi劑之反義股 不同之至少1 5個連續核苷酸。在另一實施例中，本發明係 關於如下方法’其_該組合物包含另外具有有義股之 RNAi劑，其中該有義股包含有〇、i、2或3個核苷酸與針 對選自本文提供及例如表1列出之特異性雙鏈體之P-ENaC 154740.doc -20· 201141489 的RNAi劑之有義股不同的至少15個連續核苷酸。 下文描述此實施例之多個特定具體實施例。 在一實施例中，β-ENaC相關疾病為囊腫性纖維化、i型 假醛固酮過少症（PHA1)、李德爾症候群、高血壓、驗中 毒、低鉀血症及/或肥胖相關之高血壓。 在一實施例中’ β-ENaC相關疾病為囊腫性纖維化。 在一實施例中，該方法另外包含投與額外治療。在—實 施例中’額外治療為治療有效量之組合物。 在一實施例中，額外治療為一方法（或程序）^ 在一實施例中’額外治療及RNAi劑可以任何順序投 與，或可同時投與。 在一實施例中，該方法另外包含投與用於囊腫性纖維 化、1型假醛固酮過少症（PHA1)、李德爾症候群、高血 壓、鹼中毒、低鉀血症及/或肥胖相關之高血壓之額外治 療的步驟。 在貫施例中，s亥方法另外包含投與選自以下之清單的 額外治療或療法的步驟：ENaC之其他拮抗劑、留鉀利尿 ^阿米'各利、胺苯喋啶（triamterene)、膳食鹽攝取調 即抗生素、DNase療法、沙丁胺醇（albutrol)、N-乙酿基 半胱胺酸 '呼吸療法、叩診療法及需氧運動。 在實施例中，組合物包含針對|3_ENaC之第二RNAi 夕個實％例中，第二RNAi劑與第一 RNAi劑物理上 分離^兩者物理上連接（例如共價連接或結合）。 施例中，该方法另外包含投與額外RNAi劑之步 154740.doc -21 201141489 驟，該額外RNAi劑包含有0、1、2或3個核苷酸與針對選 自本文提供及例如表1列出之特異性雙鏈體之β-ENaC的 RNAi劑之反義股不同的至少15個連續核苷酸。 使用本文所述之RNAi劑抑制β-ENaC表現之方法 在一特定實施例中，本發明係關於抑制個體中β-ENaC 基因表現之方法，包含向個體投與治療有效量之包含本發 明RNAi劑之組合物的步驟。在一實施例中，RNAi劑包含 至少一反義股，及/或包含有義及反義股，其中反義股包 含有0、1、2或3個核苷酸與針對選自本文提供及例如表i 列出之彼等特異性雙鏈體之β-ENaC的RNAi劑之反義股不 同的至少15個連續核苷酸。 下文描述本發明之此態樣的多個實施例。 在一實施例中，個體受β-ENaC相關疾病折磨或易患β_ ENaC相關疾病。 在一實施例中，β-ENaC相關疾病為囊腫性纖維化、1型 假醛固酮過少症（PHA1)、李德爾症候群 '高血壓、驗中 毒、低鉀血症及/或肥胖相關之高血壓。 在一實施例中，β-ENaC相關疾病為囊腫性纖維化。 在一實施例十，該方法另外包含投與額外治療。在一實 施例中’額外治療為治療有效量之組合物。 在一實施例中’額外治療為一方法（或程序）^ 在一實施例中，額外治療及RNAi劑可以任何順序投 與，或可同時投與。 在一實把例中，該方法另外包含投與用於囊腫性纖維 154740.doc •22· 201141489 化、1型假盤固酮過少症（PHAl) '李德爾症候群、高血 壓、驗中毒、低鉀血症及/或肥胖相關之高血壓之額外治 療的步驟。 在一實施例中，該方法另外包含投與選自以下之清單的 額外治療或療法的步驟：ENaC之其他拮抗劑、留鉀利尿 劑、阿米洛利、胺苯喋啶、膳食鹽攝取調節、抗生素、 DNase療法、沙丁胺醇（aibutrol)、N-乙醯基半脱胺酸、呼 • 吸療法、叩診療法及需氧運動。 在一實施例中’組合物包含針對β-ENaC之第二RNAi 劑。在多個實施例中，第二RNAi劑與第一 RNAi劑物理上 分離，或兩者物理上連接（例如共價連接或結合）。 在一實施例中’該方法另外包含投與額外RNAi劑之步 驟’該額外RNAi劑包含有〇、1、2或3個核苷酸與針對選 自本文提供及例如表1列出之特異性雙鏈體之p_ENaC的 RNAi劑之反義股不同的至少15個連續核苦酸。 • 針對P-ENaC之RNAi劑的醫藥調配物 在一特定實施例中，本發明係關於包含本發明RNAi劑 之組合物。在一實施例中，RNAi劑包含至少一反義股， 及/或包含有義及反義股，其中反義股包含有〇、i、2或3 個核音酸與針對選自本文提供及例如表1列出之彼等特異 性雙鏈體之β-ENaC的RNAi劑之反義股不同的至少15個連 續核苷酸，其中該組合物在醫藥學上有效之調配物中。 在一實施例中，本發明係關於RNAi劑之用途，其用於 製造用以治療β-ENaC相關疾病之藥物，其中該RNAi劑包 154740.doc •23- 201141489 含有義股及反義股，其中反義股包含有〇、1、2或3個核芽 酸與針對選自本文提供及例如表1列出之彼等特異性雙鍵 體之β-ENaC的RNAi劑之反義股不同的至少丨5個連續核苷 酸。In a particular embodiment, the invention relates to a method of treating a p_ENaC-associated disease in an individual comprising the step of administering to the individual a therapeutically effective amount of a composition comprising a RNAi agent having at least one antisense strand, wherein The sense strand comprises at least 15 consecutive nuclei having 0, 1, 2 or 3 nucleotides different from the antisense strand of the RNAi agent selected from p_ENaC of the specific duplexes provided herein and listed in Table 1, for example. Glycosylate. In another embodiment, the invention relates to a method of the invention comprising: a RNAi agent additionally having a sense strand, wherein the sense strand comprises 〇, i, 2 or 3 nucleotides and is selected At least 15 contiguous nucleotides differing from the sense strand of the RNAi agent of P-ENaC 154740.doc -20 201141489, which provides a specific duplex as listed in Table 1, for example. A number of specific embodiments of this embodiment are described below. In one embodiment, the β-ENaC-related disease is cystic fibrosis, i-type pseudoaldosteronism (PHA1), lider syndrome, hypertension, poisoning, hypokalemia, and/or obesity-related hypertension. In one embodiment, the 'beta-ENaC associated disease is cystic fibrosis. In an embodiment, the method additionally comprises administering additional treatment. In the embodiment, the additional treatment is a therapeutically effective amount of the composition. In one embodiment, the additional treatment is a method (or procedure). In one embodiment, the additional treatment and the RNAi agent can be administered in any order, or can be administered simultaneously. In one embodiment, the method additionally comprises administering a high correlation for cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and/or obesity. Additional treatment steps for blood pressure. In one embodiment, the method further comprises the step of administering an additional treatment or therapy selected from the list consisting of other antagonists of ENaC, potassium retention diuretic^Ami's, triamterene, Dietary salt intake is called antibiotics, DNase therapy, salbutamol (albutrol), N-ethyl-branched cysteine's respiratory therapy, percussion therapy, and aerobic exercise. In an embodiment, the composition comprises a second RNAi against |3_ENaC, wherein the second RNAi agent is physically separated from the first RNAi agent (e.g., covalently linked or bound). In an embodiment, the method additionally comprises the step of administering an additional RNAi agent 154740.doc -21 201141489, the additional RNAi agent comprising 0, 1, 2 or 3 nucleotides and for The antisense strands of the RNAi agent of the specific duplex of β-ENaC are listed as distinct at least 15 contiguous nucleotides. Method of inhibiting β-ENaC expression using a RNAi agent described herein In a particular embodiment, the invention relates to a method of inhibiting the expression of a β-ENaC gene in an individual comprising administering to the individual a therapeutically effective amount of a RNAi agent comprising the invention The steps of the composition. In one embodiment, the RNAi agent comprises at least one antisense strand and/or comprises a sense and antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides and is selected from For example, the antisense strands of the RNAi agent of β-ENaC of the specific duplexes listed in Table i are at least 15 contiguous nucleotides. Various embodiments of this aspect of the invention are described below. In one embodiment, the individual is afflicted with a β-ENaC-related disease or is predisposed to a β_ENaC-related disease. In one embodiment, the β-ENaC-related disease is cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome 'hypertension, detoxification, hypokalemia, and/or obesity-related hypertension. In one embodiment, the β-ENaC associated disease is cystic fibrosis. In an embodiment 10, the method additionally comprises administering additional treatment. In one embodiment, the additional treatment is a therapeutically effective amount of the composition. In one embodiment, the additional treatment is a method (or procedure). In one embodiment, the additional therapeutic and RNAi agents can be administered in any order, or can be administered simultaneously. In a practical example, the method additionally comprises administration for cystic fibers 154740.doc •22·201141489, type 1 pseudoketamine (PHAl) 'Ledel syndrome, hypertension, poisoning, low Steps for additional treatment of potassium and/or obesity-related hypertension. In one embodiment, the method further comprises the step of administering an additional treatment or therapy selected from the list consisting of other antagonists of ENaC, potassium-sparing diuretics, amiloride, ethamidine, dietary salt uptake regulation , antibiotics, DNase therapy, albuterol (aibutrol), N-acetyl sulphate, respiratory therapy, percussion therapy, and aerobic exercise. In one embodiment the composition comprises a second RNAi agent for β-ENaC. In various embodiments, the second RNAi agent is physically separated from the first RNAi agent, or both are physically linked (e.g., covalently linked or bound). In one embodiment, the method additionally comprises the step of administering an additional RNAi agent comprising guanidine, 1, 2 or 3 nucleotides and for specificity selected from the ones listed herein and listed, for example, in Table 1. The antisense strand of the duplex of the RNAi agent of p_ENaC differs by at least 15 consecutive nucleotides. • Pharmaceutical Formulations for RNAi Agents of P-ENaC In a particular embodiment, the invention relates to compositions comprising the RNAi agents of the invention. In one embodiment, the RNAi agent comprises at least one antisense strand, and/or comprises a sense and antisense strand, wherein the antisense strand comprises 〇, i, 2 or 3 nuclear acid and is selected from For example, the antisense strands of the RNAi agents of the β-ENaC of the specific duplexes listed in Table 1 are different from at least 15 contiguous nucleotides, wherein the composition is in a pharmaceutically effective formulation. In one embodiment, the invention relates to the use of a RNAi agent for the manufacture of a medicament for the treatment of a β-ENaC-related disease, wherein the RNAi agent package 154740.doc • 23- 201141489 contains a stock and an anti-sense stock, Wherein the antisense strand comprises ruthenium, 1, 2 or 3 nucleic acid different from the antisense strand of the RNAi agent selected from the β-ENaC of the specific double bond selected herein and listed in Table 1, for example. At least 5 contiguous nucleotides.

ENaC 「ENaC」意謂上皮鈉通道，由三種不同但同源之子單 元（α、β及γ)構成之膜蛋白。 ENaC存在於遠端腎元（皮層及髓質集合管）及遠端結腸之 上皮細胞之頂膜、及氣管及若干腺之***管中。ENac亦 表現於胎盤、腦及膀胱中。其提供Na+且連同位於相同細 胞之基側膜中之Na+/K+-ATPase—起自此等器官之腔室進 入上皮細胞的控制進入路徑，且負責將Na+自外部介質經 上皮細胞主動向量傳輸至胞外流體中且向血液傳輸。 ENaC位於面向腔室之頂膜上，且允許鈉自腔室移動至上 皮細胞中。經ENaC再吸收之鈉接著藉由Na+/K+-ATPase自 上皮細胞擠壓回到血流中。藉由滲透攝取水以維持怪定胞 外Na+濃度來實現ENaC對鈉的再吸收。此改變血量且隨後 影響血壓。因此，ENaC在電解質内穩定及血量與血壓控 制中起重要作用。參看例如Saxena等人，1998 Bioehem. Biophys. Res. Comm. 252: 208-213。 ENaC在表現其之多個器官中具有不同功能作用。在腎 臟（集合管）中’ Na+經ENaC之調節再吸收提供調節尿Na+排 出之主要機制’且因此允許在醛固酮之激素控制丁精密控 制整個生物體Na+平衡"藉由對頂膜電位之去極化作用， 154740.doc -24· 201141489ENaC "ENaC" means the epithelial sodium channel, a membrane protein composed of three different but homologous subunits (α, β and γ). ENaC is present in the distal ligament (the cortex and medullary collecting duct) and the apical membrane of the epithelial cells of the distal colon, as well as in the trachea and glands of several glands. ENac is also found in the placenta, brain and bladder. It provides a controlled entry pathway for Na+ and Na+/K+-ATPase in the basal membrane of the same cell from the chamber of these organs into the epithelial cells, and is responsible for the transmission of Na+ from the external medium via the epithelial active vector to In the extracellular fluid and transmitted to the blood. ENaC is located on the apical membrane facing the chamber and allows sodium to move from the chamber into the epithelial cells. The sodium resorbed by ENaC is then squeezed back into the bloodstream by epithelial cells by Na+/K+-ATPase. Resorption of sodium by ENaC is achieved by osmotic ingestion of water to maintain a strange extracellular Na+ concentration. This changes the amount of blood and then affects blood pressure. Therefore, ENaC plays an important role in electrolyte stability and blood volume and blood pressure control. See, for example, Saxena et al, 1998 Bioehem. Biophys. Res. Comm. 252: 208-213. ENaC has different functional roles in multiple organs that express it. In the kidney (collection tube), 'Na+ regulates reabsorption via ENaC to provide the primary mechanism for regulating urinary Na+ excretion' and thus allows for the sterility control of aldosterone to precisely control the entire organism's Na+ balance" by virtue of the apical membrane potential Polarization, 154740.doc -24· 201141489

Na+通道亦提供管K+分泌之驅動力。 ENaC之特異性抑制劑促進尿Na+排出且抑制Κ+分泌；此 等藥物（包括阿米洛利及胺苯喋啶）因此用作留K+利尿劑。 ENaC在遠端結腸中具有類似功能作用，防止糞便中過量 Na+損失。在氣管中，重要作用為出生時填充氣管之流體 的再吸收，促進流體分泌（出生前）轉換為流體再吸收（出生 後）。 對於囊腫性纖維化跨膜傳導調節子，其亦參與氣管中保 持黏膜清除必需之薄黏膜流體膜的對流體平衡的精密調 節。在唾液腺及汗腺的***管中，ENaC之活性傾向於降 低魯米那（luminal)Na+濃度，允許分泌鹽分較少之唾液且 防止汗液中大量損失Na+。參看例如Hummler等人，1999 Am· J. Physiol. Gastrointest· Liver Physiol· 276: 567-571 及 其中引用之參考文獻。 ENaC之序列及/或表現中之改變及突變可導致ENaC之過 度表現或高活性。假設本發明之RNAi劑藉由降低β-ENaC 含量恢復Na+再吸收經調節之平衡。The Na+ channel also provides the driving force for tube K+ secretion. Specific inhibitors of ENaC promote urinary Na+ excretion and inhibit sputum + secretion; these drugs (including amiloride and imipenem) are therefore used as residual K+ diuretics. ENaC has a similar functional role in the distal colon to prevent excessive Na+ loss in the feces. In the trachea, an important role is the reabsorption of the fluid filling the trachea at birth, promoting fluid secretion (before birth) to fluid reabsorption (after birth). For cystic fibrosis transmembrane conductance regulators, it is also involved in the precise regulation of fluid balance in the thin mucosal fluid membrane necessary for mucosal clearance in the trachea. In the excretory ducts of the salivary glands and sweat glands, the activity of ENaC tends to lower the luminal Na+ concentration, allowing the secretion of saliva with less salt and preventing a large loss of Na+ in the sweat. See, for example, Hummler et al., 1999 Am. J. Physiol. Gastrointest Liver Physiol. 276: 567-571 and references cited therein. Alterations and mutations in the sequence and/or expression of ENaC can result in excessive or high activity of ENaC. It is hypothesized that the RNAi agent of the present invention restores the adjusted balance of Na+ reabsorption by reducing the β-ENaC content.

P-ENaC 「β-ENaC」意謂基因或蛋白質阿米洛利敏感性鈉通道 子單元β(或編碼此蛋白質之任何核酸），亦不同地命名為： 鈉通道、非電壓閘控1，β ; SCNN1B ; bENaC ; ENaCb ; ENaC-β ; SCNEB 或 β-ENaC。其他識別符包括：ΟΜΙΜ: 600760 ; MGI: 104696 ; HomoloGene: 284 ;及 GeneCards: SCNN1B。可發現其他資訊：人類：Entrez 6338 ; Ensembl 154740.doc -25- 201141489 ENSG00000168447 ； UniProt P51168 ； RefSeq (mRNA) NM_000336 ； RefSeq (蛋白質）NP_000327 ； Location (UCSC) Chr 16: 23.22-23.3 Mb。小鼠：Entrez 20277 ; Ensembl ENSMUSG0000003 0873 ； UniProt Q3TP51 ；P-ENaC "β-ENaC" means the gene or protein amiloride-sensitive sodium channel subunit β (or any nucleic acid encoding this protein), also named differently: sodium channel, non-voltage gating 1, β SCNN1B; bENaC; ENaCb; ENaC-β; SCNEB or β-ENaC. Other identifiers include: ΟΜΙΜ: 600760; MGI: 104696; HomoloGene: 284; and GeneCards: SCNN1B. Additional information can be found: Human: Entrez 6338; Ensembl 154740.doc -25- 201141489 ENSG00000168447 ; UniProt P51168 ; RefSeq (mRNA) NM_000336 ; RefSeq (protein) NP_000327 ; Location (UCSC) Chr 16: 23.22-23.3 Mb. Mice: Entrez 20277; Ensembl ENSMUSG0000003 0873; UniProt Q3TP51;

RefSeq (mRNA) NM—011325 RefSeq (蛋白質）NP_035455 ;位 置（UCSC) Chr 7: 121.66-121.71 Mb。 人類β-ENaC之胺基酸序列提供於Saxena等人，1998 Biochem. Biophys. Res. Comm. 252: 208-213 中。 已描繪β-ENaC之功能域。蛋白質具有胞内N末端結構域 [胺基酸（「aa」）1至50]、第一跨膜結構域（aa 51至71)、胞 外環（aa 72至533)、第二跨膜結構域（aa 534至553)及C末端 胞内結構域（aa 5 54至640)。 C末端胞内結構域含有兩個區，其中突變與李德爾症候 群及其他疾病有關：在胺基酸564至595之區中及「PY」基 元[胺基酸共同序列？？乂丫在33(胺基酸）615至618處]。參看 例如Saxena等人· 1998 〇 本發明之β-ENaC RNAi劑可與對應於β-ENaC之特異性功 能域的一部分mRNA相互作用。在多個實施例中，本文之 RNAi劑在對應於功能域之序列中，例如在N末端胞内結構 域中，在第一跨膜結構域中，在胞外環中，在第二跨膜結 構域中或在C末端胞内結構域中，或更特定言之在胺基酸 564至595之區中，或在PY基元（胺基酸615至618)中特異性 結合於β-ENaC mRNA。 在多個實施例中，本發明之RNAi劑結合於5'或3· 154740.doc •26· 201141489 UTR(亦即未轉譯區）。 在多個實施例中，本發明之RNAi劑結合於β-ENaC mRNA，但不在對應於特定功能域之序列中，例如不在N 末端胞内結構域中、不在第一跨膜結構域中、不在胞外環 中、不在第二跨膜結構域中、或不在C末端胞内結構域 中，或更特定言之不在胺基酸564至595之區中，或不在PY 基元（胺基酸615至618)中。 在本文之實施例中，RNAi劑與β-ENaC mRNA之特定區 結合導致β-ENaC之表現、含量及/或活性降低。 RNAi劑降低β-ENaC含量之功效可例如藉由量測β-ENaC mRNA豐度或蛋白質本身含量直接量測。或者，RNAi之功 效可藉由量測β-ENaC之任何一或多種已知活性的程度或藉 由量測β-ENaC下游之路徑組分的活性改變間接量測。 蛋白質的首要活性為連同α-ENaC及γ-ENaC，及有時可 能 δ-ENaC — 起形成鈉通道 ENaC » β-ENaC、γ-ENaC 及 δ-ENaC亦可形成胰臟、睾丸及卵巢中發現之特定類型之通 道。β-ENaC亦已顯示與WWP2及NEDD4相互作用。參看例 如 McDonald等人，(2002). Am. J. Physiol. Renal Physiol. 283 (3): F431-6; Harvey等人，2001. J. Biol. Chem. 276 (11): 8597-601 ; Farr等人，（2000). Biochem. J. 345 Pt 3: 503-9。β-ENaC之活性可例如藉由其與此等其他生物組分 結合及形成功能性單元之能力量測。RNAi劑之功效亦可 藉由量測黏膜上之表面液體量且經由表現β-ENaC之組織的 組織學研究間接量測。 154740.doc -27- 201141489 多種物種中之P-ENaC序列 對β-ENaC具有特異性之RNAi劑可經設計使得其序列完 全匹配與人類β-ENaC基因及來自測試動物之同源基因對應 之mRNA的序列。因此，測試動物（例如大鼠、小鼠、石蟹 獼猴等）及人類兩者中可使用完全相同之RNAi劑。已在許 多物種中測定多種ENaC基因之序列，包括人類、小鼠、 大鼠、牛及雞，尤其如Garty等人，1997 Physiol. Rev. 77: 359-396 ;及 Ahn 等人，1999 Am. J. Physiol. 277:F121-F129 中所述。 已測定石蟹獼狼（Macizca /ajc/cM/arb，或「cyno」）之β-ENaC序列。 下文顯示cyno β-ENaC mRNA(SEQ ID NO: 221)與人類择-ENaC mRNA(SEQ ID NO: 222)序列之比對。RefSeq (mRNA) NM—011325 RefSeq (protein) NP_035455; position (UCSC) Chr 7: 121.66-121.71 Mb. The amino acid sequence of human β-ENaC is provided in Saxena et al., 1998 Biochem. Biophys. Res. Comm. 252: 208-213. The functional domain of β-ENaC has been depicted. The protein has an intracellular N-terminal domain [amino acid ("aa") 1 to 50], a first transmembrane domain (aa 51 to 71), an extracellular loop (aa 72 to 533), and a second transmembrane structure. Domain (aa 534 to 553) and C-terminal intracellular domain (aa 5 54 to 640). The C-terminal intracellular domain contains two regions, of which the mutation is associated with Riddle syndrome and other diseases: in the region of amino acids 564 to 595 and the "PY" motif [amino acid common sequence? ?乂丫 at 33 (amino acid) 615 to 618]. See, for example, Saxena et al. 1998. The β-ENaC RNAi agent of the present invention can interact with a portion of mRNA corresponding to the specific functional domain of β-ENaC. In various embodiments, the RNAi agent herein is in a sequence corresponding to a functional domain, such as in an N-terminal intracellular domain, in a first transmembrane domain, in an extracellular loop, in a second transmembrane Specific binding to β-ENaC in the domain or in the C-terminal intracellular domain, or more specifically in the region of amino acids 564 to 595, or in the PY motif (amino acids 615 to 618) mRNA. In various embodiments, the RNAi agents of the invention bind to 5' or 3·154740.doc • 26. 201141489 UTR (ie, untranslated region). In various embodiments, the RNAi agent of the invention binds to β-ENaC mRNA, but not to a sequence corresponding to a particular functional domain, such as not in the N-terminal intracellular domain, not in the first transmembrane domain, not in In the extracellular loop, not in the second transmembrane domain, or in the C-terminal intracellular domain, or more specifically in the region of the amino acid 564 to 595, or not in the PY motif (amino acid 615) To 618). In the examples herein, binding of a RNAi agent to a particular region of β-ENaC mRNA results in a decrease in the expression, content, and/or activity of β-ENaC. The efficacy of a RNAi agent to reduce the beta-ENaC content can be directly measured, for example, by measuring the abundance of beta-ENaC mRNA or the content of the protein itself. Alternatively, the effect of RNAi can be measured indirectly by measuring the extent of any one or more known activities of β-ENaC or by measuring the change in activity of the pathway components downstream of β-ENaC. The primary activity of the protein is to form sodium channels together with α-ENaC and γ-ENaC, and sometimes δ-ENaC. ENaC » β-ENaC, γ-ENaC and δ-ENaC can also be found in the pancreas, testis and ovaries. a specific type of channel. β-ENaC has also been shown to interact with WWP2 and NEDD4. See, for example, McDonald et al. (2002). Am. J. Physiol. Renal Physiol. 283 (3): F431-6; Harvey et al., 2001. J. Biol. Chem. 276 (11): 8597-601; Farr Et al. (2000). Biochem. J. 345 Pt 3: 503-9. The activity of β-ENaC can be measured, for example, by its ability to bind to other biological components and form functional units. The efficacy of the RNAi agent can also be measured indirectly by measuring the amount of surface fluid on the mucosa and by histological studies of the tissue expressing the β-ENaC. 154740.doc -27- 201141489 P-ENaC sequences in a variety of species RNAi agents specific for β-ENaC can be designed such that their sequences match the mRNA corresponding to the human β-ENaC gene and homologous genes from test animals. the sequence of. Therefore, the same RNAi agent can be used in both test animals (e.g., rats, mice, rock crab macaques, etc.) and humans. The sequences of various ENaC genes have been determined in a number of species, including humans, mice, rats, cows and chickens, especially as Garty et al., 1997 Physiol. Rev. 77: 359-396; and Ahn et al., 1999 Am. J. Physiol. 277: F121-F129. The β-ENaC sequence of the stone crab wolf (Macizca / ajc/cM/arb, or "cyno") has been determined. The alignment of the cyno β-ENaC mRNA (SEQ ID NO: 221) with the human select-ENaC mRNA (SEQ ID NO: 222) sequence is shown below.

Cyn〇P-ENaC ------------;-------------------------------------- 人類 β-ENaC GTGCTTCCCCGCCCCTGAACCTGCTCCCTCCCAGTCGGTCTCGCCGCGCT 50Cyn〇P-ENaC ------------;-------------------------------- ------ Human β-ENaC GTGCTTCCCCGCCCCTGAACCTGCTCCCTCCCAGTCGGTCTCGCCGCGCT 50

Cyno β-ENaC 人類卜ENaC -----------------------------------GGTACCCAGCTTGCT 15 CGCCGGGTGTCCCAGTGTCACCAACACTCGGCCGCCGCCGCCAGCTTGGC 100 * **★* + *★★Cyno β-ENaC Humans ENaC -----------------------------------GGTACCCAGCTTGCT 15 CGCCGGGTGTCCCAGTGTCACCAACACTCGGCCGCCGCCGCCAGCTTGGC 100 * **★ * + *★★

Cyno β-ENaC TGTTCTTTTTGCAGAAGCTCAGAATAAACGCTCAACTTTGGCAGATCAAT 65 AM β-ENaC GCGCACCGCCGCCTCCGCCACCGCCGACAGCGCGCATCCTCCGTGTCCCC 150 it* ★★ 1r ★★ it * * **Cyno β-ENaC TGTTCTTTTTGCAGAAGCTCAGAATAAACGCTCAACTTTGGCAGATCAAT 65 AM β-ENaC GCGCACCGCCGCCTCCGCCACCGCCGACAGCGCGCATCCTCCGTGTCCCC 150 it* ★★ 1r ★★ it * * **

Cynoβ-ENaC 人類卜ENaC TCCCCGGGGATCCGA-ATTCGCCACCATGCACGTGAAGAAGTACCTGCTG 114 GCTCCGCCGCCCGAGCAGGTGCCACTATGCACGTGAAGAAGTACCTGCTG 200 4r Hr *· * ★禽 ★ ★★★★★ ***★★★*****★★**********★Cynoβ-ENaC Humans ENaC TCCCCGGGGATCCGA-ATTCGCCACCATGCACGTGAAGAAGTACCTGCTG 114 GCTCCGCCGCCCGAGCAGGTGCCACTATGCACGTGAAGAAGTACCTGCTG 200 4r Hr *· * ★ Avian ★ ★★★★★ ***★★★*****★★**********★

Cynoβ-ENaC 人類^-ENaC AAGTGCCTGCACCGGCTGCAGAAGGGCCCCGGCTACACGTACAAGGAGCT 164 AAGGGCCTGCATCGGCTGCAGAAGGGCCCCGGCTACACGTACAAGGAGCT 250 * * * ★ it iCynoβ-ENaC Human^-ENaC AAGTGCCTGCACCGGCTGCAGAAGGGCCCCGGCTACACGTACAAGGAGCT 164 AAGGGCCTGCATCGGCTGCAGAAGGGCCCCGGCTACACGTACAAGGAGCT 250 * * * ★ it i

Cyno β-ENaC GCTGGTGTGGTACTGCGATAACACCAACACCCACGGCCCCAAGCGTATCA 214 人類 β-ENaC GCTGGTGTGGTACTGCGACAACACCAACACCCACGGCCCCAAGCGCATCA 300 ★★★★★★★★★★★★★★★★★★ ★★★★去4★★★★★夤夤★★★★Cyno β-ENaC GCTGGTGTGGTACTGCGATAACACCAACACCCACGGCCCCAAGCGTATCA 214 Human β-ENaC GCTGGTGTGGTACTGCGACAACACCAACACCCACGGCCCCAAGCGCATCA 300 ★★★★★★★★★★★★★★★★★★ ★★★★去4★★★★★夤夤★★★★

Cyno β-ENaC TCTGCGAGGGGCCCAAGAAGAAAGCCGTGTGGTTCCTGCTCACCCTGCTC 264 人類 β-ENaC TCTGTGAGGGGCCCAAGAAGAAAGCCATGTGGTTCCTGCTCACCCTGCTC 350 -28- 154740.doc 201141489Cyno β-ENaC TCTGCGAGGGGCCCAAGAAGAAAGCCGTGTGGTTCCTGCTCACCCTGCTC 264 Human β-ENaC TCTGTGAGGGGCCCAAGAAGAAAGCCATGTGGTTCCTGCTCACCCTGCTC 350 -28- 154740.doc 201141489

Ογηοβ-ENaC 人類β-ENaCΟγηοβ-ENaC Human β-ENaC

TTCACTGCTCTCGTCTGCTGGCAGTGGGGCATCTTCATCAGGACCTACTT TTCGCCGCCCTCGTCTGCTGGCAGTGGGGCATCTTCATCAGGACCTACTT 314 400TTCACTGCTCTCGTCTGCTGGCAGTGGGGCATCTTCATCAGGACCTACTT TTCGCCGCCCTCGTCTGCTGGCAGTGGGGCATCTTCATCAGGACCTACTT 314 400

Cyn〇P~ENaC 人類g-ENaCCyn〇P~ENaC Human g-ENaC

gagctgggaggtcagcGtctccctctccgtaggcttcaagaccatggact GAGCTGGGAGGTCAGCGTCTCCCTCTCCGTAGGCTTCAAGACCATGGACT 364 450gagctgggaggtcagcGtctccctctccgtaggcttcaagaccatggact GAGCTGGGAGGTCAGCGTCTCCCTCTCCGTAGGCTTCAAGACCATGGACT 364 450

Cyn〇3-ENaC 人類卜ENaCCyn〇3-ENaC Human Bud ENaC

TCCCCGCCGTCACCATCTGCAATGCTAGCCCCTTCAAGTATTCCAAAGTC TCCCTGCCGTCACCATCTGCAATGCTAGCCCCTTCAAGTATTCCAAAATC 414 500TCCCCGCCGTCACCATCTGCAATGCTAGCCCCTTCAAGTATTCCAAAGTC TCCCTGCCGTCACCATCTGCAATGCTAGCCCCTTCAAGTATTCCAAAATC 414 500

Ογηοβ-ENaC人類&-ENaC AAGCATTTGCTGAAGGACCTGGATGAGCTGATGGAAGCTGTCCTGGAGAG AAGCATTTGCTGAAGGACCTGGATGAGCTGATGGAAGCTGTCCTGGAGAG ★★★★★★★★★★★★★★★★★★★★★★★★♦★★★★★★★★★★★★★★★★★★★★★★★★Λ 464 550Ογηοβ-ENaC Human &-ENaC AAGCATTTGCTGAAGGACCTGGATGAGCTGATGGAAGCTGTCCTGGAGAG AAGCATTTGCTGAAGGACCTGGATGAGCTGATGGAAGCTGTCCTGGAGAG ★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★ ★★★★★★★★★Λ 464 550

Cynoβ-ENaC 人類卜ENaC AATCCTGGCTCCTGAGCTAAGCCATGCCAATGCCACCAGGACCCTGAACT AATCCTGGCTCCTGAGCTAAGCCATGCCAATGCCACCAGGAACCTGAACT **************·*★**********★******·******** ********* 514 600Cynoβ-ENaC Humans ENaC AATCCTGGCTCCTGAGCTAAGCCATGCCAATGCCACCAGGACCCTGAACT AATCCTGGCTCCTGAGCTAAGCCATGCCAATGCCACCAGGAACCTGAACT **************·*★**********★******·******* * ********* 514 600

Cynoβ-ENaC人類g-ENaCCynoβ-ENaC human g-ENaC

CTTCCATCTGGAACCACACACCACTGGTCCTTATTGATGAACGGAACCCC TCTCCATCTGGAACCACACACCCCTGGTCCTTATTGATGAACGGAACCCC 564 650CTTCCATCTGGAACCACACACCACTGGTCCTTATTGATGAACGGAACCCC TCTCCATCTGGAACCACACACCCCTGGTCCTTATTGATGAACGGAACCCC 564 650

Cyno β-ENaC 人類卜ENaCCyno β-ENaC Human Bu ENaC

CACCACCCCATGGTCCTCGATCTCTTTGGAGATAACCACAATGGCTTAAC CACCACCCCATGGTCCTTGATCTCTTTGGAGACAACCACAA.TGGCTTAAC 614 700CACCACCCCATGGTCCTCGATCTCTTTGGAGATAACCACAATGGCTTAAC CACCACCCCATGGTCCTTGATCTCTTTGGAGACAACCACAA.TGGCTTAAC 614 700

Cyno β-ENaC 人類β-ENaCCyno β-ENaC Human β-ENaC

AAACAGCTCAGCATCAGAAAAGATCTGTAATGCCCATGGGTGCAAAATGG AAGCAGCTCAGCATCAGAAAAGATCTGTAATGCCCACGGGTGCAAAATGG 664 750AAACAGCTCAGCATCAGAAAAGATCTGTAATGCCCATGGGTGCAAAATGG AAGCAGCTCAGCATCAGAAAAGATCTGTAATGCCCACGGGTGCAAAATGG 664 750

Cyno β-ENaC 人類卜ENaCCyno β-ENaC Human Bu ENaC

Cyno β-ENaC 人類卜ENaC CCATGAGACTATGTAGCCTCAACGGGACCCAGTGCACCTTCCGGAACTTC 714 CCATGAGACTATGTAGCCTCAACAGGACCCAGTGTACCTTCCGGAACTTC 800 ACCAGCGCTACCCAGGCAGTGACAGAGTGGTACAGCCTGCAGGCCACCAA 764 ACCAGTGCTACCCAGGCATTGACAGAGTGGTACATCCTGCAGGCCACCAA 850Cyno β-ENaC Humans ENaC CCATGAGACTATGTAGCCTCAACGGGACCCAGTGCACCTTCCGGAACTTC 714 CCATGAGACTATGTAGCCTCAACAGGACCCAGTGTACCTTCCGGAACTTC 800 ACCAGCGCTACCCAGGCAGTGACAGAGTGGTACAGCCTGCAGGCCACCAA 764 ACCAGTGCTACCCAGGCATTGACAGAGTGGTACATCCTGCAGGCCACCAA 850

Cynoβ-ENaC人類g-ENaC CATCTTTGCGCAGGTGCCGCAGCAGGAGCTGGTGGAGATGAGCTACCCCG 814 CATCTTTGCACAGGTGCCACAGCAGGAGCTAGTAGAGATGAGCTACCCCG 90 0Cynoβ-ENaC Human g-ENaC CATCTTTGCGCAGGTGCCGCAGCAGGAGCTGGTGGAGATGAGCTACCCCG 814 CATCTTTGCACAGGTGCCACAGCAGGAGCTAGTAGAGATGAGCTACCCCG 90 0

Cynoβ-ENaC 人類b-ENaC GCGAGCAGATGATCCTGGCCTGCCTGTTTGGAGCTGAGCCCTGCAACTAC 864 GCGAGCAGATGATCCTGGCCTGCCTATTCGGAGCTGAGCCCTGCAACTAC 950Cynoβ-ENaC Human b-ENaC GCGAGCAGATGATCCTGGCCTGCCTGTTTGGAGCTGAGCCCTGCAACTAC 864 GCGAGCAGATGATCCTGGCCTGCCTATTCGGAGCTGAGCCCTGCAACTAC 950

Cynoβ-ENaC CGGAACTTCACGTCCATCTTCTACCCTCACTATGGCAACTGTTACATCTT 914 人類卜 ENaC CGGAACTTCACGTCCATCTTCTACCCTCACTATGGCAACTGTTACATCTT 1000 ★ ★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★if**·* cynoβ-ENaC CAACTGGGGCATGACAGAGAAGGCACTTCCTTCGGCCAACCCTGGACCTG 964 人類卜 ENaC CAACTGGGGCATGACAGAGAAGGCACTTCCTTCGGCCAACCCTGGAACTG 1050 cyno β-ENaC AATTTGGCCTGAAGTTGATCCTGGACATAGGCCAGGAAGACTACGTCCCC 1014 人類 β-ENaC AATTCGGCCTGAAGTTGATCCTGGACATAGGCCAGGAAGACTACGTCCCC 1100 29- 154740.doc 201141489Cynoβ-ENaC CGGAACTTCACGTCCATCTTCTACCCTCACTATGGCAACTGTTACATCTT 914 Humans ENaC CGGAACTTCACGTCCATCTTCTACCCTCACTATGGCAACTGTTACATCTT 1000 ★ ★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★ ★★★★★★ if ** · * cynoβ-ENaC CAACTGGGGCATGACAGAGAAGGCACTTCCTTCGGCCAACCCTGGACCTG 964 BU human ENaC CAACTGGGGCATGACAGAGAAGGCACTTCCTTCGGCCAACCCTGGAACTG 1050 cyno β-ENaC AATTTGGCCTGAAGTTGATCCTGGACATAGGCCAGGAAGACTACGTCCCC 1014 human β-ENaC AATTCGGCCTGAAGTTGATCCTGGACATAGGCCAGGAAGACTACGTCCCC 1100 29- 154740.doc 201141489

Cyno β-ENaC β-ENacCyno β-ENaC β-ENac

TTCCTCGCGTCCACGGCTGGGGTCAGGCTGATGCTTCACGAGCAGAGGTC TTCCTTGCGTCCACGGCCGGGGTCAGGCTGATGCTTCACGAGCAGAGGTC 1064 1150TTCCTCGCGTCCACGGCTGGGGTCAGGCTGATGCTTCACGAGCAGAGGTC TTCCTTGCGTCCACGGCCGGGGTCAGGCTGATGCTTCACGAGCAGAGGTC 1064 1150

Cyno β-ENaC 人類卜ENaCCyno β-ENaC Human Bu ENaC

ATACCCCTTCATCAGAGACGAGGGCATCTATGCCATGTCGGGGACAGAGA ATACCCCTTCATCAGAGATGAGGGCATCTACGCCATGTCGGGGACAGAGA 11141200ATACCCCTTCATCAGAGACGAGGGCATCTATGCCATGTCGGGGACAGAGA ATACCCCTTCATCAGAGATGAGGGCATCTACGCCATGTCGGGGACAGAGA 11141200

Cynoβ-ENac 人類卜ENaCCynoβ-ENac Human Bud ENaC

Cyno β-ENaC 人鈕匕-ENaC CGTCCATCGGGGTACTCGTGGACAAGCTTCAGCGCATGGGGGAGCCCTAC 1164 CGTCCATCGGGGTACTCGTGGACAAGCTTCAGCGCATGGGGGAGCCCTAC 1250Cyno β-ENaC human button 匕-ENaC CGTCCATCGGGGTACTCGTGGACAAGCTTCAGCGCATGGGGGAGCCCTAC 1164 CGTCCATCGGGGTACTCGTGGACAAGCTTCAGCGCATGGGGGAGCCCTAC 1250

AGCCCGTGCACCGTGAATGGCTCCGAGGTCCCCGTCCAAAACTTCTACAG AGCCCGTGCACCGTGAATGGTTCTGAGGTCCCCGTCCAAAACTTCTACAGAGCCCGTGCACCGTGAATGGCTCCGAGGTCCCCGTCCAAAACTTCTACAG AGCCCGTGCACCGTGAATGGTTCTGAGGTCCCCGTCCAAAACTTCTACAG

：AAAAC 1214 1300:AAAAC 1214 1300

Cynoβ-ENac 人類g-ENaCCynoβ-ENac human g-ENaC

TGACTACAACACGACCTACTCCATCCAGGCCTGTCTTCGCTCCTGCTTCC TGACTACAACACGACCTACTCCATCCAGGCCTGTCTTCGCTCCTGCTTCC 1264 1350TGACTACAACACGACCTACTCCATCCAGGCCTGTCTTCGCTCCTGCTTCC TGACTACAACACGACCTACTCCATCCAGGCCTGTCTTCGCTCCTGCTTCC 1264 1350

Cynoβ-ENac 人類卜ENac AAGACCACATGATCCGTAGCTGCAAGTGTGGGCACTACCTCTACCCACTG 1314 AAGACCACATGATCCGTAACTGCAACTGTGGCCACTACCTGTACCCACTG 1400 CCCCGTGGGGAGAAATACTGCAACAACCGGGACTTCCCAGACTGGGCCCA 1364 CCCCGTGGGGAGAAATACTGCAACAACCGGGACTTCCCAGACTGGGCCCA 1450 *****************************************务********Cynoβ-ENac Humans ENac AAGACCACATGATCCGTAGCTGCAAGTGTGGGCACTACCTCTACCCACTG 1314 AAGACCACATGATCCGTAACTGCAACTGTGGCCACTACCTGTACCCACTG 1400 CCCCGTGGGGAGAAATACTGCAACAACCGGGACTTCCCAGACTGGGCCCA 1364 CCCCGTGGGGAGAAATACTGCAACAACCGGGACTTCCCAGACTGGGCCCA 1450 ************************************ *****************

Cynoβ-ENaC 人類β-ENacCynoβ-ENaC Human β-ENac

Cynoβ-ENaC 人類β-ENac TTGCTACTCAGATCTGCAGATGAGCGTGGCGCAGAGAGAGACCTGCATTG ttgctactcagatctacagatgagcgtggcgcagagagagacctgcattg 1414 1500Cynoβ-ENaC Human β-ENac TTGCTACTCAGATCTGCAGATGAGCGTGGCGCAGAGAGAGACCTGCATTG ttgctactcagatctacagatgagcgtggcgcagagagagacctgcattg 1414 1500

Cyno β-ENaC 人類卜ENaC GCATGTGCAAGGAATCCTGCAATGACACCCAGTAC7VAGATGACTATCTCC 1464 GCATGTGCAAGGAGTCCTGCAATGACACCCAGTACAAGATGACCATCTCC 1550Cyno β-ENaC Humans ENaC GCATGTGCAAGGAATCCTGCAATGACACCCAGTAC7VAGATGACTATCTCC 1464 GCATGTGCAAGGAGTCCTGCAATGACACCCAGTACAAGATGACCATCTCC 1550

Cynoβ-ENaC 人類g-ENaC ATGGCTGACTGGCCTTCTGAGGCCTCTGAGGACTGGATTTTCCACGTCTT 1514 ATGGCTGACTGGCCTTCTGAGGCCTCCGAGGACTGGATTTTCCACGTCTT 1600 ★ ★****★*★★**★★★★★*★*★★★★** ★★★***·****★**★****★*★**Cynoβ-ENaC Human g-ENaC ATGGCTGACTGGCCTTCTGAGGCCTCTGAGGACTGGATTTTCCACGTCTT 1514 ATGGCTGACTGGCCTTCTGAGGCCTCCGAGGACTGGATTTTCCACGTCTT 1600 ★ ★****★*★★**★★★★★*★*★★★★** ★★★★★★★* *★****★*★**

Cyno β-ENac 人類卜ENaCCyno β-ENac Human Bu ENaC

Cynoβ-ENaC 人類卜ENaC GTCTCAGGAGCGGGACCAAAGCACCAATATCACCCTGAGCAGGAAGGGAA 1564 GTCTCAGGAGCGGGACCAAAGCACCAATATCACCCTGAGCAGGAAGGGAA 1650 ★ ★★★★★★★★ir***·*************** ** ********************** TTGTCAAGCTCAACATCTACTTCCAAGAATTTAACTATCGCACCATTGAA 1614 TTGTCAAGCTCAACATCTACTTCCAAGAATTTAACTATCGCACCATTGAA 1700Cynoβ-ENaC Humans ENaC GTCTCAGGAGCGGGACCAAAGCACCAATATCACCCTGAGCAGGAAGGGAA 1564 GTCTCAGGAGCGGGACCAAAGCACCAATATCACCCTGAGCAGGAAGGGAA 1650 ★ ★★★★★★★★ir***·*************** ** ********* ************* TTGTCAAGCTCAACATCTACTTCCAAGAATTTAACTATCGCACCATTGAA 1614 TTGTCAAGCTCAACATCTACTTCCAAGAATTTAACTATCGCACCATTGAA 1700

Cyno β-ENaC 人類卜ENaC GAATCAGCAGCCAATAACCTCGTCTGGCTGCTCTCAAATCTGGGTGGCCA GAATCAGCAGCCAATAACATCGTCTGGCTGCTCTCGAATCTGGGTGGCCA ★ ★★★★**★**★★★★★**会★ ★ 1664 1750Cyno β-ENaC Humans ENaC GAATCAGCAGCCAATAACCTCGTCTGGCTGCTCTCAAATCTGGGTGGCCA GAATCAGCAGCCAATAACATCGTCTGGCTGCTCTCGAATCTGGGTGGCCA ★ ★★★★**★**★★★★★**★★★ 1664 1750

Cynoβ-ENaC 人類β-ENac cynoβ-ENaC 人類β-ENacCynoβ-ENaC Human β-ENac cynoβ-ENaC Human β-ENac

Cyno β-ENaC 人類b-ENaC GTTTGGCTTCTGGATGGGGGGCTCTGTGCTGTGCCTCATCGAGTTTGGGG 1714 GTTTGGCTTCTGGATGGGGGGCTCTGTGCTGTGCCTCATCGAGTTTGGGG 1800 AGATCATCATCGACTTTGTGT^SGATCACCATCATCAAGCTGGTGGCCTTG 17 64 AGATCATCATCGACTTTGTGTGGATCACCATCATCAAGCTGGTGGCCTTG 1850 GCCAAGAGCCTCCGGCAGCGGCGAGCCCAAGCCAGCTACTCCGGCCCACC 1814 GCCAAGAGCCTACGGCAGCGGCGAGCCCAAGCCAGCTACGCTGGCCCACC 1900 ★ ★★★★★★★★★★ ★★★<*★★★★★★★★<*★★★★★★★★★★★★★★ ★ ★«★★★★★★ 154740.doc •30· 201141489Cyno β-ENaC human b-ENaC GTTTGGCTTCTGGATGGGGGGCTCTGTGCTGTGCCTCATCGAGTTTGGGG 1714 GTTTGGCTTCTGGATGGGGGGCTCTGTGCTGTGCCTCATCGAGTTTGGGG 1800 AGATCATCATCGACTTTGTGT ^ SGATCACCATCATCAAGCTGGTGGCCTTG 17 64 AGATCATCATCGACTTTGTGTGGATCACCATCATCAAGCTGGTGGCCTTG 1850 GCCAAGAGCCTCCGGCAGCGGCGAGCCCAAGCCAGCTACTCCGGCCCACC 1814 GCCAAGAGCCTACGGCAGCGGCGAGCCCAAGCCAGCTACGCTGGCCCACC 1900 ★ ★★★★★★★★★★ ★★★ < * ★★★★★★★★ < *★★★★★★★★★★★★★★ ★ ★«★★★★★★ 154740.doc •30· 201141489

Cyno β-ENaC 人類g-ENaCCyno β-ENaC Human g-ENaC

GCCCACGGTGGCTGAGCTGGTGGAGGCCCACACCAACTTCGGCTACCAGC GCCCACCGTGGCCGAGCTGGTGGAGGCCCACACCAACTTTGGCTTCCAGC 1864 1950GCCCACGGTGGCTGAGCTGGTGGAGGCCCACACCAACTTCGGCTACCAGC GCCCACCGTGGCCGAGCTGGTGGAGGCCCACACCAACTTTGGCTTCCAGC 1864 1950

Cyno β-ENaC 人類g-EMaCCyno β-ENaC Human g-EMaC

CTGACACGGCCCCCCGCAGCCCCAACACCGGGCCCTACCCCAGTGAGCAG CTGACACGGCCCCCCGCAGCCCCAACACTGGGCCCTACCCCAGTGAGCAG 1914 2000CTGACACGGCCCCCCGCAGCCCCAACACCGGGCCCTACCCCAGTGAGCAG CTGACACGGCCCCCCGCAGCCCCAACACTGGGCCCTACCCCAGTGAGCAG 1914 2000

Cynoβ-ENaC GCCCTGCCCATCCCGGGCACCCCGCCCCCCAACTATGACTCCCTGCGTCT 1964 人類卜ENaC GCCCTGCCCATCCCAGGCACCCCGCCCCCCAACTATGACTCCCTGCGTCT 2050 cynoβ-ENaC GCAGCCACTGGACGTCATCGAGTCTGACAGTGAGGGTGATGCCATCTAA- 2013 人類 β-ENaC GCAGCCGCTGGACGTCATCGAGTCTGACAGTGAGGGTGATGCCATCTAAC 2100 ★★★★★★ ★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★★Cynoβ-ENaC GCCCTGCCCATCCCGGGCACCCCGCCCCCCAACTATGACTCCCTGCGTCT 1964 BU human ENaC GCCCTGCCCATCCCAGGCACCCCGCCCCCCAACTATGACTCCCTGCGTCT 2050 cynoβ-ENaC GCAGCCACTGGACGTCATCGAGTCTGACAGTGAGGGTGATGCCATCTAA- 2013 human β-ENaC GCAGCCGCTGGACGTCATCGAGTCTGACAGTGAGGGTGATGCCATCTAAC 2100 ★★★★★★ ★★★★★★★★★★★★★★★★★★★★★★ ★★★★★★★★★★★★★★★★★★★★

Cynoβ-ENaC ——GCGGCCGCCTAG——AAATAGCTTGATCTGGTTA--CCACTAAACCA 2055 人類 β-EMaC CCTGCCCCTGCCCACCCCGGGCGGCTGAAACTCACTGAGCAGCCAAGACT 2150 ★ it * k ★ ie it * ★ ★ * ★ * it * ★ * * *Cynoβ-ENaC ——GCGGCCGCCTAG——AAATAGCTTGATCTGGTTA--CCACTAAACCA 2055 Human β-EMaC CCTGCCCCTGCCCACCCCGGGCGGCTGAAACTCACTGAGCAGCCAAGACT 2150 ★ it * k ★ ie it * ★ ★ * ★ * it * ★ * * *

Cyno β-ENaC GC—CTCAAGAACAC-CCGAATGGAGTCTCT----AAGCTACATAATACC 2098 人類 β-ENaC GTTGCCCGAGGCCTCACTGTATGGTGCCCTCTCCAAAGGGTCGGGAGGGT 2200 ★ ir ★ ** ★去★ a ★★奢★ * ★ **★ * *Cyno β-ENaC GC—CTCAAGAACAC-CCGAATGGAGTCTCT----AAGCTACATAATACC 2098 Human β-ENaC GTTGCCCGAGGCCTCACTGTATGGTGCCCTCTCCAAAGGGTCGGGAGGGT 2200 ★ ir ★ ** ★ Go ★ a ★ ★ Extravagant ★ * ★ **★ * *

Cyno β-ENaC AAGTTACACTTTACAAAATGTTGTCCCCCAA-AATGTAGCCATTCGTATC 2147 人類 β-ENaC AGCTCTCCAGGCCAGAGCTTGTGTCCTTCAACAGAGAGGCCAGCGGCAAC 2250 ★ ★★ ★ ★ * ★★★ ★ ★ ★★★★ * * ★Cyno β-ENaC AAGTTACACTTTACAAAATGTTGTCCCCCAA-AATGTAGCCATTCGTATC 2147 Human β-ENaC AGCTCTCCAGGCCAGAGCTTGTGTCCTTCAACAGAGAGGCCAGCGGCAAC 2250 ★ ★★ ★ ★ ★ ★★★ ★ ★ ★★★★ * * ★

Cyno β-ENaC TGCTCCTAATAAAAAGAAAGTTTCTTCACATTCTAAAAAAAAAAAAAAAA 2197 人類 β-ENaC TGGTCCGTTACTGGCCAAGGGCTCTGTAGAATCACGGTGCTGGTACAGGA 2300 * * * * * ★ * ★ ★ ** + ★ ** * ★ ★Cyno β-ENaC TGCTCCTAATAAAAAGAAAGTTTCTTCACATTCTAAAAAAAAAAAAAAAA 2197 Human β-ENaC TGGTCCGTTACTGGCCAAGGGCTCTGTAGAATCACGGTGCTGGTACAGGA 2300 * * * * * ★ * ★ ★ ** + ★ ** * ★ ★

Cyno β-ENaC AAAAAAAAAAAAAAAAAACCCCCCCC--CCCCCCCCCCTGCAGAGATCTG 2245 人類 β-ENaC TGCAGGAATAAATTGTATCTTCACCTGGTTCCTACCCTCGTCCCTACCTG 2350 * ** **★ ***** *★ cyno β-ENaC CTAGCTTGAGTATTCTATAGAGTCACCTAAATACT--------------- 2280 人類 β-EMaC TCCTGATCCTGGTCCTGAAGACCCCTCGGAACACCCTCTCCTGGTGGCAG 2400 * * ** *** * * ** **Cyno β-ENaC AAAAAAAAAAAAAAAAAACCCCCCCC--CCCCCCCCCCTGCAGAGATCTG 2245 Human β-ENaC TGCAGGAATAAATTGTATCTTCACCTGGTTCCTACCCTCGTCCCTACCTG 2350 * ** **★ ***** *★ cyno β-ENaC CTAGCTTGAGTATTCTATAGAGTCACCTAAATACT--------------- 2280 Human β-EMaC TCCTGATCCTGGTCCTGAAGACCCCTCGGAACACCCTCTCCTGGTGGCAG 2400 * * ** *** * * ** **

Cyno β-ENac -------------------------------------------------- 人類 β-ENaC GCCACTTCCCTCCCAGTGCCAGTCTCCATCCACCCCAGAGAGGAACAGGC 2450Cyno β-ENac ---------------------------------------------- ---- Human β-ENaC GCCACTTCCCTCCCAGTGCCAGTCTCCATCCACCCCAGAGAGGAACAGGC 2450

Cyno β-ENaC -------------------------------------------------- 人類 β-ENac GGGTGGGCCATGTGGTTTTCTCCTTCCTGGCCTTGGCTGGCCTCTGGGGC 2500Cyno β-ENaC ---------------------------------------------- ---- Human β-ENac GGGTGGGCCATGTGGTTTTCTCCTTCCTGGCCTTGGCTGGCCTCTGGGGC 2500

Cyno β-ENac -------------------------------------------------- 人類 β-ENaC AGGGGTGGTGGAGAGATGGAAGGGCATCAGGTGTAGGGACCCTGCCAAGT 2550Cyno β-ENac ---------------------------------------------- ---- Human β-ENaC AGGGGTGGTGGAGAGATGGAAGGGCATCAGGTGTAGGGACCCTGCCAAGT 2550

Cyno β-ENaC ----------------------------------------------- 人類 β-ENaC GGCACCTGATTTACTCTAGAAAATAAAAGTAGAAAATACTGAGTCCA 2597Cyno β-ENaC ---------------------------------------------- - Human β-ENaC GGCACCTGATTTACTCTAGAAAATAAAAGTAGAAAATACTGAGTCCA 2597

Cynoβ-ENaC (SEQ ID NO: 221) 人類卜ENaC (SEQ ID NO： 222) cyno及人類序列之起始（ATG)及終止（TAA)密碼子加下 線。人類及cyno序列之間的核苷酸匹配以星號（*)標記。 在一實施例中，本發明之β-ENaC RNAi劑包含與人類 -31 154740.doc 201141489 大鼠及cyno β-ENaC mRNA—致之序列。此序列一致性便 於在人類測試之前的動物測試。在另一實施例中，P_ENaC RNAi劑包含與人類、小鼠及cyno β·ΕΝπ mRNA—致之序 列。 針對P-ENaC之RNAi劑的其他實施例 在—實施例中’ β-ENaC RNAi劑包含與任何其他mRNA 或基因之彼等不匹配的序列。在一實施例中，p_ENac RNAi劑包含與所有其他已知非-β-ENaC mRNA或基因至少 有〇、1、2或3個核苷酸不同的序列。 在一實施例中’向有需要之患者（例如罹患囊腫性纖維 化、1型假醛固酮過少症（PHA1)、李德爾症候群、高血 壓、鹼中毒、低鉀血症及肥胖相關之高血壓之患者）投與 本發明之β-ENaC RNAi劑。 亦可向患者投與一種以上對β-ENaC具有特異性之RNAi 劑。在一實施例中，本發明之p_ENaC RNAi劑可視情況連 同一或多種適於彼疾病之額外醫藥劑一起投與。在一實施 例中，本發明之β-ENaC RNAi劑可視情況連同任何其他適 當額外治療一起投與’其中額外治療可為組合物或方法。 在囊腫性纖維化、1型假醛固酮過少症（PHA1)、李德爾 症候群、高血壓、鹼中毒、低鉀血症及/或肥胖相關之高 血麼之情形中，RNAi劑及額外疾病治療可以任何順序同 時或依序投與’或隨時間以一或多次給藥投與。 定義 為方便起見，下文提供用於本發明、實例及隨附申請專 154740.doc •32- 201141489 利範圍之某些術語及短語的含義。若術語在本發明其他部 分中之用法與本部分提供之其定義之間存在明顯差異，則 應以本部分之定義為主。 RNAi 劑Cynoβ-ENaC (SEQ ID NO: 221) Human EN ENaC (SEQ ID NO: 222) cyno and human sequence initiation (ATG) and termination (TAA) codons were added. Nucleotide matches between human and cyno sequences are marked with an asterisk (*). In one embodiment, the β-ENaC RNAi agent of the present invention comprises a sequence which is responsive to human-31 154740.doc 201141489 rat and cyno β-ENaC mRNA. This sequence identity is convenient for animal testing prior to human testing. In another embodiment, the P_ENaC RNAi agent comprises a sequence that is responsive to human, mouse, and cyno β·ΕΝπ mRNA. Other Examples of RNAi Agents Against P-ENaC In the Examples - the β-ENaC RNAi agents comprise sequences that do not match any of the other mRNAs or genes. In one embodiment, the p_ENac RNAi agent comprises a sequence that differs from all other known non-beta-ENaC mRNAs or genes by at least 1、, 1, 2 or 3 nucleotides. In one embodiment, 'to patients in need (eg, suffering from cystic fibrosis, type 1 pseudoaldosteronism (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and obesity-related hypertension Patient) is administered the β-ENaC RNAi agent of the present invention. More than one RNAi agent specific for β-ENaC can also be administered to the patient. In one embodiment, the p_ENaC RNAi agent of the present invention may optionally be administered in conjunction with one or more additional pharmaceutical agents suitable for the disease. In one embodiment, the β-ENaC RNAi agent of the invention may optionally be administered in conjunction with any other suitable additional treatment, wherein the additional treatment may be a composition or method. In the case of cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia and/or obesity-related hyperemia, RNAi agents and additional disease treatments can Any order is administered simultaneously or sequentially 'or with one or more administrations over time. Definitions For convenience, the meanings of certain terms and phrases used in the scope of the invention, examples, and accompanying application 154740.doc • 32- 201141489 are provided below. If there is a significant difference between the usage of the term in other parts of the invention and its definition provided in this section, it should be based on the definition in this section. RNAi agent

在一實施例中，本發明係關於β-ENaC RNAi劑或包含至 少一與β-ENaC核酸（或其部分）互補之反義核酸序列的其他 組合物，或係關於編碼siRNA之重組表現載體或包含可充 當如下文定義之RNAi的反義核酸的組合物。如本文所 用，「反義」核酸包含與編碼β-ENaC蛋白質之「有義」核 酸互補的核苷酸序列（例如與雙股DNA之編碼股互補、與 mRNA互補或與β-ENaC基因或核酸之編碼股互補）》 如本文所用，術語「針對β-ENaC之RNAi劑」、「對β-ENaC具有特異性之RNAi劑」、「針對β-ENaC之iRNA劑」、 「針對β-ENaC之siRNA」、「β-ENaC siRNA」及其類似術語 係指siRNA(短抑制RNA)、shRNA(短或小髮夾RNA)、 iRNA(干擾 RNA)劑、RNAi(RNA 干擾）劑、dsRNA(雙股 RNA)、微RNA及其類似物，且係指特異性靶向β-ENaC mRNA、對β-ENaC mRNA具有特異性及/或結合於β-ENaC mRNA之組合物。如本文戶斤用，術語「反義核酸」或「包 含反義核酸之組合物」及其類似術語欲廣泛地涵蓋包含至 少一個對其目標反義之核酸股的任何組合物；此包括（但 不限於）任何 siRNA、shRNA、iRHA、dsRNA、微RNA、反 義寡核苷酸、及包含反義核酸之任何其他組合物。如本文 所用，術語「iRNA」及「RNAi」係指含有RNA(或其衍生 154740.doc -33- 201141489 物）之試劑，且其介導另一 RNA轉錄物經RNA誘導沉默複 合物（RISC)路徑靶向裂解。在一實施例中，RNAi劑為活化 RISC複合物/路徑之寡核苷酸組合物。在另一實施例中， RNAi劑包含反義股序列（反義寡核苷酸）。 本發明之RNAi劑乾向（例如結合於、黏結於等）p_ENac mRNA。使用對p_ENaC具有特異性之RNAi劑導致β-ENaC 活性、含量及/或表現降低’例如「阻斷」或「基因剔 除」目標基因或目標序列。尤其在一實施例中，在疾病狀 態特徵為β-ENaC過度表現或高活性的情形中，投與針對β_ ENaC之RNAi劑充分阻斷p_ENaC目標以恢復正常程度之ρ_ ENaC活性及/或正常程度之Na+再吸收。 在一實施例中’ RNAi包含單股（諸如如本文所述之 shRNA)。 在多個實施例中，對一股或兩股切口。 在一實施例中，單股RNAi劑寡核苷酸或聚核苷酸可包 含有義版及/或反義股。參看例如Si〇ud 2005 J. Mol. Biol. 348:1079-1090，及其中引用之參考文獻。因此，本發明涵 蓋RNAi劑，其中單股包含本文所述之RNAi劑的有義股或 反義股。 尤其適用於本發明之siRNA包括可特異性結合於p_ENaC mRNA之區且具有一或多個以下品質之彼等：在p_ENaC之 編碼區段中結合；在5·未轉譯區之接合點及編碼區段之起 點處或附近結合；在mRNA之轉譯起始位點處或附近結 合；在外顯子及内含子之接合點處、跨越該等接合點或在 154740.doc •34· 201141489 該等接合點附近結合；與mRNA或其他基因之轉錄物幾乎 不結合或不結合（幾乎無或無「脫靶作用」）；在非雙股之 £域或主幹區中或附近結合於β-ENaC mRNA，例如在環或 單股部分；幾乎不或不引起免疫原性；在多個動物物種In one embodiment, the invention relates to a β-ENaC RNAi agent or other composition comprising at least one antisense nucleic acid sequence complementary to a β-ENaC nucleic acid (or a portion thereof), or to a recombinant expression vector encoding an siRNA or A composition comprising an antisense nucleic acid that can serve as RNAi as defined below. As used herein, an "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a β-ENaC protein (eg, complementary to a coding strand of a double stranded DNA, complementary to an mRNA, or to a β-ENaC gene or nucleic acid). Coding strands complementary) As used herein, the terms "RNAi agent for β-ENaC", "RNAi agent specific for β-ENaC", "iRNA agent for β-ENaC", "for β-ENaC siRNA", "β-ENaC siRNA" and similar terms refer to siRNA (short inhibitory RNA), shRNA (short or small hairpin RNA), iRNA (interfering RNA) agent, RNAi (RNA interference) agent, dsRNA (double strand) RNA), microRNAs and analogs thereof, and refers to compositions that specifically target β-ENaC mRNA, are specific for β-ENaC mRNA, and/or bind to β-ENaC mRNA. As used herein, the terms "antisense nucleic acid" or "composition containing an antisense nucleic acid" and the like are intended to broadly encompass any composition comprising at least one nucleic acid strand that is antisense to its target; this includes (but not Limited to any siRNA, shRNA, iRHA, dsRNA, microRNA, antisense oligonucleotide, and any other composition comprising an antisense nucleic acid. As used herein, the terms "iRNA" and "RNAi" refer to an agent that contains RNA (or its derivative 154740.doc-33-201141489) and mediates another RNA transcript via RNA-induced silencing complex (RISC). Path-targeted lysis. In one embodiment, the RNAi agent is an oligonucleotide composition that activates the RISC complex/path. In another embodiment, the RNAi agent comprises an antisense strand sequence (antisense oligonucleotide). The RNAi agents of the invention dry (e.g., bind to, bind to, etc.) p_ENac mRNA. The use of a RNAi agent specific for p_ENaC results in a decrease in β-ENaC activity, content and/or performance' such as "blocking" or "gene knockout" target gene or target sequence. Particularly in an embodiment, in the case where the disease state is characterized by excessive expression or high activity of β-ENaC, administration of the RNAi agent against β_ENaC substantially blocks the p_ENaC target to restore normality of ρ_ENaC activity and/or normality. Na+ reabsorbs. In one embodiment 'RNAi comprises a single strand (such as shRNA as described herein). In various embodiments, one or two slits are applied. In one embodiment, a single strand of RNAi oligonucleotide or polynucleotide may comprise a positive and/or antisense strand. See, for example, Si〇ud 2005 J. Mol. Biol. 348: 1079-1090, and references cited therein. Thus, the invention encompasses RNAi agents, wherein the single strand comprises a sense strand or an antisense strand of the RNAi agent described herein. Particularly suitable siRNAs for use in the present invention include those which specifically bind to the region of p_ENaC mRNA and which have one or more of the following qualities: binding in the coding region of p_ENaC; junctions and coding regions in the 5 untranslated region Binding at or near the beginning of the segment; binding at or near the translation start site of the mRNA; at the junction of the exon and intron, across the junction, or at 154740.doc •34· 201141489 Binding near the point; hardly binding or not binding to the transcript of mRNA or other genes (nearly no or no "off-target"); binding to β-ENaC mRNA in or near the non-double-stranded or stem region, eg In the ring or single-stranded part; hardly or not causing immunogenicity; in multiple animal species

(包括人類、小鼠、大鼠、cyno等）之間保守的p_ENaC mRNA序列之區段中結合，因為存在保守序列便於使用多 種貫驗室動物測試；結合於mRNA之雙股區；結合於at含 集區（例如至少約 50、51、52、53、54、55、56、57、 58、59或60% AT富集）；及/或缺乏已知或懷疑降 活性之特定序列，例如在5,端存在GG序列，其可減少 siRNA之雙股部分的分離。在一實施例中，對p_ENaC具有 特異性之RNAi可為具有任何一或多種此等品質之雙股 RNA。 如本文所用之術語「雙股RNA」或「dsRNA」係指包含 第一及第二股之；例如包括rna分子或具有雜交 雙鏈體區（亦即第一股及第二股之核普酸鹼基配對的區）之 分子複合物的組合物，其包含兩個反平行及實質上互補之 核酸股，其將稱為關於目標RNA具有「有義」及「反義」 方向。關於抓财目標之反義股亦稱為「引導（guide)」 月又且有義股亦稱為「過客（passenger)」股。過客股可包 括以下中之至少-或多纟：相較於其他股之一或多個外核 苦酸(例如***物(bulge)或i nt環）、相較於其他股之切 口、間隙寺。在多個音始^丨占 固貫施例中’ RNAi劑包含第一股及第Binding in a segment of the conserved p_ENaC mRNA sequence (including human, mouse, rat, cyno, etc.), since the presence of conserved sequences facilitates the use of multiple laboratory animal assays; binding to the double-stranded region of mRNA; binding to at Containing a collection (eg, at least about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% AT enrichment); and/or lacking a specific sequence of known or suspected activity, such as in 5, a GG sequence is present at the end, which reduces the separation of the double strands of the siRNA. In one embodiment, the RNAi specific for p_ENaC can be a double-stranded RNA having any one or more of these qualities. The term "dual-stranded RNA" or "dsRNA" as used herein, is meant to include the first and second strands; for example, including rna molecules or having hybridized duplex regions (ie, the first and second strands of nucleotides) A composition of a molecular complex of base-paired regions comprising two anti-parallel and substantially complementary nucleic acid strands which will be referred to as having a "sense" and "antisense" orientation with respect to the target RNA. Anti-sense stocks that focus on catching money are also known as "guides". Months and stocks are also known as "passengers". The passenger shares may include at least one or more of the following: compared to one or more of the other stocks (eg, bulge or i nt ring), incisions compared to other stocks, gap temples . In the case of multiple sounds, the 'RNAi agent contains the first and the first

二股。在多個實施例φ 银 η„ Λ . M ]中第一叔為有義股且第二股為反義 154740.doc -35- 201141489 股。在其他實施例中，第— 股0 股為反義股且第二股為有 義 雙鏈體區可具有允許經Rlsr 路徑特異性降解所要 RNA之任何長度，但長度 要目標 ,「u 、 又通常將在9至36個鹼基對Two shares. In the various embodiments φ silver η „ Λ . M ] the first uncle is a stock and the second stock is an antisense 154740.doc -35 - 201141489 shares. In other embodiments, the first stock is reversed The sense strand and the second strand of the sense duplex region may have any length that allows for specific degradation of the desired RNA via the Rlsr pathway, but the length is targeted, "u, which will usually be between 9 and 36 base pairs.

(「bp」），例如15-30 bp範圍中。者 T 亏慮9至36 bp之雙鏈體， 該雙鏈體可為在此範圍中的任何長度’例如9、ι〇 " 12、13、14、15、16、17、18、19、2〇、21 22 23 : 24、25、26、27、28、29、3〇、31、32333435、或 36 bp及其間的任何子範圍，包括（但不限於）ΐ5·3〇 bp、& 26 bp、 15-23 bp、 15-22 bp、 15-21 bp、 15_2〇 bp、 1519 bp、15-18 bp、15-17 bp ' 18-30 bp、18_26 冲、i8 23 bp、18-22 bp、18-21 bp、18-20 bp、19-3〇 bp、19_26 bp 、 19-23 bp 、 19-22 bp 、 19-21 bp ' 19-20 bp 、 19 bp 、 20_30 bp、20-26 bp、20_25 bp、20-24 bp、20-23 bp、20 22 bp、20-21 bp、20驗基對、21-30 bp、21-26 bp、21-25 bp、21-24 bp、21-23 bp、21-22 bp、21 bp、22 bp 或 23 bp。藉由以Dicer及類似酶處理在細胞中產生之dsRNA長度 一般在約19至約22 bp的範圍中。dsRNA之雙鏈體區的一股 包含與目標RNA之一區實質上互補的序列。形成雙鏈體結 構之兩股可來自具有至少一個自補雙鏈體區之單個RNA分 子，或可由雜交形成雙鏈體之兩個或兩個以上單獨RNA分 子形成。若雙鏈體區由單個分子的兩個自補區形成’分子 可具有在形成雙鏈體結構之一股的3'端與另一股的5'端之 間由核苷酸之單股鏈分開之雙鏈體區（本文稱為「髮夾 154740.doc -36 - 201141489 環」，例如shRNA結構中所發現）。髮夾環可包含至少一個 未配對核苷酸；在一些實施例中，髮夾環可包含至少3、 至少4、至少5、至少6、至少7、至少8、至少9、至少10、 至少20、至少23或23個以上未配對核苷酸。若dsRNA之兩 個實質上互補之股由單獨RNA分子構成，則彼等分子無需 (但可）共價連接。若兩股經髮夾環共價連接，則該構造在 本文及此項技術中一般稱為「shRNA」。若兩股藉助於除 了髮夾環之外的結構共價連接，則連接結構稱為「連接 子」。 RNA干擾 RNA干擾（RNAi)為轉錄後靶向基因沉默技術，其使用雙 股RNA(dsRNA)降級含有與dsRNA相同之序列的信使 RNA(mRNA)。RNAi過程出現在核糖核酸酶III(Dicer)將較 長dsRNA裂解成較短片段（稱為siRNA)時。siRNA(小干擾 RNA)通常約21至23個核苷酸長且包含約19個鹼基對雙鏈 體。較小RNA區段接著介導目標mRNA之降解。Dicer亦已 涉及於自轉錄控制中所牽涉之保守結構之前驅物RNA切除 21-及22-核苷酸小時序RNA(stRNA)中。Hutvagner等人， 2001，Science，293，834。RNAi反應特徵亦為核酸内切酶 複合物，通常稱為RNA誘導沉默複合物（RISC)，其介導與 siRNA之反義股互補的單股mRNA之裂解。目標RNA之裂 解在與siRNA雙鏈體之反義股互補的區中部發生。 在一態樣中，RNA干擾劑包括與目標RNA序列相互作用 以定向目標RNA之裂解的單股RNA。不希望受理論約束， 154740.doc -37- 201141489 引入植物及無脊椎動物細胞中之長雙股RNA藉由稱為 Dicer之III型核酸内切酶斷裂成siRNA(Sharp等人，Genes Dev. 2001，15:485)。Dicer，一 種核糖核酸酶 III樣酶，將 dsRNA處理成特徵為2個鹼基3'懸垂物的19-23鹼基對短干 擾 RNA(Bernstein 等人，（2001) Nature 409:363)。siRNA 接 著併入至RNA誘導沉默複合物（RISC)，其中一或多種解螺 旋酶展開siRNA雙鏈體，使目前未配對之siRNA股中之一 者能夠用作「引導」股以引導目標辨識（Nykanen等人， (2001) Cell 107:3 09)。在反義引導股與適當目標mRNA結 合時，RISC内之一或多個核酸内切酶使目標裂解以誘導沉 默（Elbashir 等人，（2001) Genes Dev. 15:188)。因此，在一 態樣中，本發明係關於促進形成RISC複合物以實現目標基 因之沉默的單股RNA。 亦已在多個系統中研究RNA干擾。對果蠅 胚胎溶解產物進行的研究（Elbashir等人，2001 EMBO J. 20: 6877及Tuschl等人，國際PCT公開案第WO 01/75 164號）已 揭示對siRNA長度、結構、化學成分、及序列的特定要 求，其為介導多個系統（尤其包括哺乳動物）中之有效RNAi 活性所必需。此等研究已顯示當含有3'末端二核苷酸懸垂 物時21-核苷酸siRNA雙鏈體最具活性。容許以2'-去氧核 苷酸（2'-H)取代3'末端siRNA懸垂物核苷酸。此外，siRNA 雙鏈體之目標互補股上之5'-磷酸酯一般為siRNA活性所 需。對於治療用途而言最重要的是，短於50 bp或50 bp左 右之siRNA雙鏈體不會活化哺乳動物細胞中之干擾素反 154740.doc -38 · 201141489 應。參看例如Tuschl等人，WO 01/752164。 本文所述之dsRNA分子（RNAi劑）因此適用於p_ENaC之 RNA干擾。 RNAi劑之特徵：有義股、反義股及（可選）懸垂物 在多個實施例中，RNAi劑包含第一股及第二股，例如 有義股及反義股，且雙鏈體之一端或兩端視情況含有本文 稱為懸垂物之未配對核苷酸。 術語「反義股」係指包括與目標序列實質上互補之區域 的RNAi劑之股。如本文所用，術語「互補區」係指反義 股上如本文中所定義與例如目標序列之序列實質上互補的 區域。若互補區與目標序列不完全互補，則分子内部或末 端區令可存在錯配。一般而言，最容許之錯配在末端區， 例如在5及/或3末端之5、4、3或2個核普酸内。 如本文所用，術語「有義股」係指包括與反義股之區域 貫質上互補之區域的RNAi劑之股，如上文定義之術語。 基因之序列可隨個體變化，尤其在編碼區段内之擺動位 置處，或在未轉譯區；個體之編碼序列亦可彼此不同，在 mRNA中產生其他差異。在需要時，RNAi劑之有義股及反 義股的序列因此可經設計以對應於個別患者之序列。 RNAi劑之序列亦可經修飾以降低免疫原性、與非所要 mRNA之結合（例如「脫靶作用」）或提高在血液中之穩定 性。此等序列變異體與RNAi劑之鹼基或5，或3,或其他端-帽 端之化學改質無關。 RNAi劑亦可具有〇' 個懸垂物之懸垂物；在〇加懸 154740.doc •39· 201141489 垂物之情形中’其為鈍端的。RNAi劑可具有0、1或2個鈍 端。在「鈍端RNAi劑」中，兩股皆以鹼基對終止；因此 純端分子缺乏3'或5'單股核苷酸懸垂物。 如本文所用’術語「懸垂物」或「核苷酸懸垂物」係指 自RNAi劑之雙鏈體結構之兩股中至少一者之末端突出的 至少一個未配對核苷酸。舉例而言，當dsRNA之一股的3' 端延伸超過另一股之5'端，或反之亦然，則未配對核苷酸 形成懸垂物。dsRNA可包含至少一個核苷酸的懸垂物；或 者懸垂物可包含至少兩個核苷酸、至少三個核苷酸、至少 四個核苷酸、至少五個核苷酸或五個以上核苷酸。懸垂物 可包含核苷酸/核苷類似物（包括去氧核苷酸/核苷）或由核 苷酸/核苷類似物（包括去氧核苷酸/核苷）組成。懸垂物可 在有義股、反義股或其任何組合上。此外，懸垂物之核發 酸可存在於dsRNA之反義股或有義股的5,端、3,端或兩端 上。 RNAi劑亦可視情況包含帽端。術語「帽端」及其類似 術語包括與雙股核苷酸雙鏈體末端連接之化學部分，但在 本文使用時’排除為核苷酸或核苷之化學部分^ r 3，帽端」 連接於核苷酸或寡核苷酸的3,端處《「5,帽端」連接於核苷 酸或寡核普酸的5 ’端處。在一實施例中’ 3'端帽端如例如 WO 2005/021749及 W0 2007/128477 中揭示。 本發明因此涵蓋對包含RNAi劑中之反義股（其可連續或 經連接子或環連接）的β-ENaC具有特異性之RNAi劑。在一 更特定實施例中，RNAi劑包含反義股及有義股，其一起 154740.doc -40· 201141489 實施例中，亦可視情況包含1或2 端。RNAi劑用於誘導β-ENaC之 包含雙股或互補區。在一 個懸垂物及/或1或2個帽 RNA干擾。 目標及互補序列 本發明之RNAi劑靶向（例如特異性結合於、黏結於等）編 碼基因β-ENaC之mRNA。使用對p-ENaC具有特異性之 RNAi劑導致β-ENaC活性、含量及/或表現降低，例如「阻 斷」或「基因剔除」目標基因或目標序列◊尤其在一實施 例中，在疾病狀態特徵為β-ENaC過度表現或高活性的情形 中’投與針對β-ENaC之RNAi劑充分阻斷β-ENaC基因以恢 復正常程度之β-ENaC活性及/或正常程度之Na+再吸收。("bp"), for example in the range of 15-30 bp. T is deficient in a 9 to 36 bp duplex, which may be of any length in this range 'eg 9, ι〇" 12, 13, 14, 15, 16, 17, 18, 19, 2〇, 21 22 23 : 24, 25, 26, 27, 28, 29, 3〇, 31, 32333435, or 36 bp and any subranges therebetween, including but not limited to ΐ5·3〇bp, & 26 bp, 15-23 bp, 15-22 bp, 15-21 bp, 15_2 bp, 1519 bp, 15-18 bp, 15-17 bp '18-30 bp, 18_26 rush, i8 23 bp, 18-22 Bp, 18-21 bp, 18-20 bp, 19-3 bp, 19_26 bp, 19-23 bp, 19-22 bp, 19-21 bp '19-20 bp, 19 bp, 20_30 bp, 20-26 Bp, 20_25 bp, 20-24 bp, 20-23 bp, 20 22 bp, 20-21 bp, 20 base pair, 21-30 bp, 21-26 bp, 21-25 bp, 21-24 bp, 21 -23 bp, 21-22 bp, 21 bp, 22 bp or 23 bp. The length of the dsRNA produced in the cells by treatment with Dicer and similar enzymes is generally in the range of from about 19 to about 22 bp. A strand of the duplex region of the dsRNA comprises a sequence that is substantially complementary to a region of the target RNA. The two strands forming the duplex structure may be derived from a single RNA molecule having at least one self-complementing duplex region, or two or more separate RNA molecules that may be hybridized to form a duplex. If the duplex region is formed by two self-complementing regions of a single molecule, the molecule may have a single strand of nucleotides between the 3' end of one of the strands forming the duplex structure and the 5' end of the other strand. A separate duplex region (referred to herein as "hairpin 154740.doc -36 - 201141489 loop", as found in the shRNA structure). The hairpin loop can comprise at least one unpaired nucleotide; in some embodiments, the hairpin loop can comprise at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20 At least 23 or more unpaired nucleotides. If two substantially complementary strands of dsRNA are composed of separate RNA molecules, then they are not (but can) covalently link. If the two hairpin loops are covalently linked, the construct is generally referred to herein as "shRNA". If the two strands are covalently joined by means of a structure other than the hairpin loop, the joint structure is referred to as a "linker". RNA interference RNA interference (RNAi) is a post-transcriptional targeted gene silencing technique that uses double-stranded RNA (dsRNA) to downgrade messenger RNA (mRNA) containing the same sequence as dsRNA. The RNAi process occurs when ribonuclease III (Dicer) cleaves longer dsRNA into shorter fragments (called siRNA). siRNA (small interfering RNA) is typically about 21 to 23 nucleotides in length and contains about 19 base pair duplexes. The smaller RNA segment then mediates degradation of the target mRNA. Dicer has also been implicated in the conserved structure involved in transcriptional control prior to excision RNA excision in 21- and 22-nucleotide small-sequence RNA (stRNA). Hutvagner et al, 2001, Science, 293, 834. The RNAi response is also characterized by an endonuclease complex, commonly referred to as the RNA-induced silencing complex (RISC), which mediates the cleavage of a single strand of mRNA complementary to the antisense strand of siRNA. The cleavage of the target RNA occurs in the middle of the region complementary to the antisense strand of the siRNA duplex. In one aspect, the RNA interference agent comprises a single strand of RNA that interacts with a target RNA sequence to direct cleavage of the target RNA. Without wishing to be bound by theory, 154740.doc -37- 201141489 Long double-stranded RNA introduced into plants and invertebrate cells is cleaved into siRNA by a type III endonuclease called Dicer (Sharp et al., Genes Dev. 2001) , 15: 485). Dicer, a ribonuclease III-like enzyme, processes dsRNA into a 19-23 base pair short-interference RNA characterized by a 2 base 3' overhang (Bernstein et al., (2001) Nature 409:363). The siRNA is then incorporated into an RNA-induced silencing complex (RISC) in which one or more helicases are deployed to siRNA duplexes, enabling one of the currently unpaired siRNA strands to be used as a "guided" strand to guide target recognition ( Nykanen et al. (2001) Cell 107:3 09). Upon binding of the antisense leader strand to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir et al., (2001) Genes Dev. 15: 188). Thus, in one aspect, the invention relates to single-stranded RNA that facilitates the formation of a RISC complex to achieve silencing of a target gene. RNA interference has also been studied in multiple systems. Studies on lysates of Drosophila embryos (Elbashir et al, 2001 EMBO J. 20: 6877 and Tuschl et al, International PCT Publication No. WO 01/75 164) have revealed siRNA length, structure, chemical composition, and The specific requirements of the sequence are necessary to mediate efficient RNAi activity in multiple systems, including mammals in particular. These studies have shown that 21-nucleotide siRNA duplexes are most active when containing a 3' terminal dinucleotide pendant. The 3'-end siRNA suspension nucleotides are allowed to be substituted with 2'-deoxynucleotide (2'-H). In addition, the 5'-phosphate on the target complementary strand of the siRNA duplex is generally required for siRNA activity. For therapeutic use, the most important is that siRNA duplexes shorter than 50 bp or 50 bp do not activate interferon in mammalian cells. 154740.doc -38 · 201141489 should. See, for example, Tuschl et al., WO 01/752164. The dsRNA molecules (RNAi agents) described herein are therefore suitable for RNA interference of p_ENaC. Characteristics of RNAi agents: sense strands, antisense strands, and (optionally) drape. In various embodiments, the RNAi agent comprises a first strand and a second strand, such as a sense strand and an antisense strand, and the duplex One or both ends optionally contain unpaired nucleotides referred to herein as pendants. The term "antisense strand" refers to a strand of RNAi agent that includes a region that is substantially complementary to the sequence of interest. As used herein, the term "complementary region" refers to a region on an antisense strand that is substantially complementary to, for example, a sequence of a target sequence as defined herein. If the complementary region is not completely complementary to the target sequence, there may be a mismatch in the internal or terminal region of the molecule. In general, the most permissible mismatch is in the terminal region, for example within 5, 4, 3 or 2 nucleotides at the 5 and/or 3 ends. As used herein, the term "sense stock" refers to a strand of RNAi agent that includes a region that is complementary to the region of the antisense strand, as defined above. The sequence of the gene may vary from individual to individual, particularly at the swing position within the coding region, or in the untranslated region; the individual coding sequences may also differ from each other, producing other differences in the mRNA. The sequences of the sense and antisense strands of the RNAi agent can therefore be designed to correspond to the sequence of individual patients, as desired. The sequence of the RNAi agent can also be modified to reduce immunogenicity, binding to undesired mRNA (e.g., "off-target") or to increase stability in the blood. These sequence variants are not related to the base of the RNAi agent or the chemical modification of the 5, or 3, or other end-caps. The RNAi agent may also have a pendant of 〇' overhangs; it is blunt-ended in the case of 〇 154 740.doc • 39· 201141489 pits. The RNAi agent can have 0, 1 or 2 blunt ends. In the "blunt-end RNAi agent", both strands are terminated by base pairs; therefore, the pure-end molecule lacks a 3' or 5' single-nucleotide pendant. The term "overhang" or "nucleotide drape" as used herein refers to at least one unpaired nucleotide that protrudes from the end of at least one of the two strands of the duplex structure of the RNAi agent. For example, when the 3' end of one of the dsRNA strands extends beyond the 5' end of the other strand, or vice versa, the unpaired nucleotides form a pendant. The dsRNA may comprise a pendant of at least one nucleotide; or the overhang may comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more than five nucleosides acid. The overhang may comprise or consist of a nucleotide/nucleoside analog (including deoxynucleotides/nucleosides) or a nucleotide/nucleoside analog (including deoxynucleotides/nucleosides). The overhang can be on the stock, antisense stock or any combination thereof. In addition, the nucleus acid of the overhang may be present at the 5, 3, 3, or both ends of the antisense strand or the sense strand of the dsRNA. The RNAi agent may also include a cap end as appropriate. The term "cap end" and the like includes a chemical moiety attached to the end of a double-stranded nucleotide duplex, but as used herein, 'excluded as a nucleotide or a chemical moiety of a nucleoside ^r 3, cap end" linkage At the 3' end of the nucleotide or oligonucleotide, "5, the cap end" is attached to the 5' end of the nucleotide or oligonucleotide. In one embodiment the '3' end cap ends are disclosed, for example, in WO 2005/021749 and WO 2007/128477. The invention thus encompasses RNAi agents which are specific for β-ENaC comprising an antisense strand in a RNAi agent which may be contiguous or linked by a linker or loop. In a more specific embodiment, the RNAi agent comprises an antisense strand and a sense strand, together with 154740.doc -40. 201141489. In the examples, it may optionally include 1 or 2 ends. The RNAi agent is used to induce the inclusion of a double-stranded or complementary region of β-ENaC. Interference in a drape and / or 1 or 2 cap RNA. Target and Complementary Sequences The RNAi agents of the invention target (e.g., specifically bind to, bind to, etc.) the mRNA encoding the gene β-ENaC. The use of a RNAi agent specific for p-ENaC results in a decrease in β-ENaC activity, content and/or performance, such as "blocking" or "knockout" of a target gene or target sequence, especially in an embodiment, in a disease state In the case where β-ENaC is overexpressed or highly active, the administration of a RNAi agent against β-ENaC substantially blocks the β-ENaC gene to restore normal levels of β-ENaC activity and/or normal Na+ reabsorption.

如本文所用，「目標序列」或「目標基因」係指轉錄基 因（例如β-ENaC基因）期間形成之mRNA分子（包括為初級轉 錄產物之RNA加工產物之mRNA)的核苷酸序列之連續部 分。序列之目標部分將至少足夠長以用作彼部分處或附近 之iRNA定向裂解的受質。舉例而言，目標序列一般長度 將為9-3 6個核普酸（「nt」），例如15 -3 0 nt，包括其間之所 有子範圍。作為非限制性實例，目標序列可為15-30 nt、 15-26 nt、15-23 nt、15-22 nt、15-21 nt、15-20 nt、15-19 nt、15-18 nt、15-17 nt、18-30 nt、18-26 nt、18-23 nt' 18-22 nt、18-21 nt、18-20 nt、19-30 nt、19-26 nt、19-23 nt 、 19-22 nt 、 19-21 nt 、 19-20 nt 、 19 nt 、 20-30 nt 、 20- 26 nt、20-25 nt、20-24 nt、20-23 nt ' 20-22 nt、20-21 nt ' 20 nt 、 21-30 nt 、 21-26 nt 、 2卜25 nt 、 21-24 nt 、 21- 154740.doc •41 · 201141489 23 nt 或 21-22 nt、21 nt、22 nt 或 23 nt。RNAi 之有義股及 ，反義股包含與目標核酸p_ENaC之序列互補的序列。 如本文所用，且除非另外指出，否則術語「互補」係指 包含第一核苷酸序列之寡核苷酸或聚核苷酸在特定條件下 與包含第二核苷酸序列之寡核苷酸或聚核苷酸雜交且形成 雙鏈體結構之能力。該等條件可例如為嚴格條件，例如As used herein, "target sequence" or "target gene" refers to a contiguous portion of the nucleotide sequence of an mRNA molecule (including mRNA that is an RNA processing product of a primary transcript) formed during a transcriptional gene (eg, the β-ENaC gene). . The target portion of the sequence will be at least long enough to serve as a substrate for the targeted cleavage of iRNA at or near the portion. For example, the target sequence will typically be 9-3 6 nucleotides ("nt"), such as 15 - 30 nt, including all subranges in between. As a non-limiting example, the target sequence can be 15-30 nt, 15-26 nt, 15-23 nt, 15-22 nt, 15-21 nt, 15-20 nt, 15-19 nt, 15-18 nt, 15-17 nt, 18-30 nt, 18-26 nt, 18-23 nt' 18-22 nt, 18-21 nt, 18-20 nt, 19-30 nt, 19-26 nt, 19-23 nt, 19-22 nt, 19-21 nt, 19-20 nt, 19 nt, 20-30 nt, 20-26 nt, 20-25 nt, 20-24 nt, 20-23 nt ' 20-22 nt, 20- 21 nt ' 20 nt , 21-30 nt , 21-26 nt , 2 卜 25 nt , 21-24 nt , 21- 154740.doc •41 · 201141489 23 nt or 21-22 nt, 21 nt, 22 nt or 23 Nt. The sense strand of RNAi and the antisense strand comprise a sequence complementary to the sequence of the target nucleic acid p_ENaC. As used herein, and unless otherwise indicated, the term "complementary" refers to an oligonucleotide or polynucleotide comprising a first nucleotide sequence under certain conditions and an oligonucleotide comprising a second nucleotide sequence. Or the ability of a polynucleotide to hybridize and form a duplex structure. Such conditions can be, for example, stringent conditions, such as

400 mM Naa、40 mM PIPES pH 6.4、1 福 EDTA、5(TC 或70°C持續12-16小時，隨後洗滌。可應用諸如生物體内 可能遭遇之生理學相關條件的其他條件。熟習此項技術者 將能夠決定最適於根據雜交核苷酸之最終應用的兩序列互 補性測試之條件設定。 如本文所用，「互補」序列亦可包括非Watson-Crick鹼基 對及/或由非天然及經修飾核苷酸形成之鹼基對，或完全 由該等驗基對形成’在滿足上文關於其雜交能力之要求的 範圍内。該等非Watson-Crick鹼基對包括（但不限於）G:U Wobble或Hoogstein驗基配對。 另外關於dsRNA之有義股與反義股之間，或RNAi劑之反 義股與標靶序列之間的鹼基匹配可使用本文之術語「互 補」、「完全互補」及「實質上互補」，如將自其使用之上 下文理解。 如本文所用，與信使RNA(mRNA)的「至少一部分實質 上互補」之聚核苷酸係指與所關注mRNA(例如編碼β-ENaC之mRNA)之連續部分實質上互補之聚核苷酸。舉例 而言，若序列與編碼β-ENaC之mRNA的不中斷部分實質上 154740.doc -42- 201141489 互補’則聚核苷酸與β-ENaC mRNA的至少一部分互補。 RNAi劑内（例如如本文所述之dsRNA内）之互補序列包括 在一或兩個核苷酸序列之整個長度上鹼基配對之包含第一 核苷酸序列的寡核苷酸或聚核苷酸與包含第二核苷酸序列 的寡核苷酸或聚核苷酸。該等序列在本文中可稱為彼此 「完全互補」。然而，若在本文中第一序列稱為與第二序 列「實質上互補」，則兩個序列可完全互補，或其在雜交 高達30個鹼基對之雙鏈體時可形成一或多個，但一般不超 過5、4 ' 3或2個錯配鹼基對，同時保持在最貼近其最終應 用之條件下雜交的能力’例如經RISC路徑抑制基因表現。 然而，若兩個募核苷酸經設計以在雜交時形成一或多個單 股懸垂物’則關於互補性判定而言，不應認為該等懸垂物 錯配。舉例而言’為本文所述之目的而言，包含一個長度 為21個核苷酸之寡核苷酸及另一長度為23個核苷酸之寡核 苷酸’且其中較長寡核苷酸包含與較短寡核苷酸完全互補 之21個核苷酸之序列的雙鏈體仍可稱為「完全互補如 上文所述’術語懸垂物描述雙股核苷酸雙鏈體之3，或5 •端 處之未配對核苷酸。在一實施例中，懸垂物為〇至4 nt長且 在3'端上。 因此’本發明之RNAi劑與目標p_ENaC中之目標序列互 補或實質上互補且為雙股的，包含有義股及反義股（其可 連續，經環連接或接合），其中雙股區為9至36 #長（尤其 例如19·22 bp或19-23 bp長），且此外可視情況包含3，或5，懸 垂物，且RNAi劑此外可包含3,帽端^ RNAi劑介導尺1^八干 154740.doc -43- 201141489 擾，下調或抑制β-ENaC之含量、表現及/或活性，及/或建 立或重建大致正常程度之ENaC及/或β-ENaC活性，或與 ENaC相關之其他生物功能。 降低p-ENaC含量、表現及/或活性之RNAi劑 乾向β-ENaC之RNAi劑包括結合於本文提供之p_ENaC序 列及用於經RNAi機制降低β-ENaC之彼等。針對p-ENaCi 例示性siRNA提供於例如表1中。 本發明之RNAi劑使β-ENaC基因沉默、抑制、下調及/或 抑止β-ENaC基因之表現’使得實現大致正常程度之β_ ENaC活性、表現及/或含量及/或Na+再吸收。 此外，在多個實施例中，視疾病病況及生物環境而定， 可接受使用本發明之RNAi劑建立低於正常程度或高於正 常程度之程度的β-ENaC表現、活性及/或含量。400 mM Naa, 40 mM PIPES pH 6.4, 1 EDTA, 5 (TC or 70 ° C for 12-16 hours, followed by washing. Other conditions such as physiologically relevant conditions that may be encountered in the organism may be applied. The skilled artisan will be able to determine the conditions that are best suited for the two-sequence complementarity test based on the final application of the hybrid nucleotide. As used herein, a "complementary" sequence may also include non-Watson-Crick base pairs and/or from non-natural and The base pairs formed by the modified nucleotides, or formed entirely by the pair of testers, are within the scope of satisfying the above requirements for their ability to hybridize. Such non-Watson-Crick base pairs include, but are not limited to, G: U Wobble or Hoogstein test pairing. In addition, the base matching between the sense strand and the antisense strand of the dsRNA, or the antisense strand of the RNAi agent and the target sequence can be used in the term "complementary", "Completely complementary" and "substantially complementary" as understood in the context of its use. As used herein, a polynucleotide that is "substantially complementary" to at least a portion of messenger RNA (mRNA) refers to the mRNA of interest ( For example encoding β-ENaC A polynucleotide in which a contiguous portion of the mRNA is substantially complementary. For example, if the sequence is complementary to the uninterrupted portion of the mRNA encoding β-ENaC, substantially 154740.doc -42- 201141489, then the polynucleotide and β- At least a portion of the ENaC mRNA is complementary. The complement of a sequence within a RNAi agent (eg, within a dsRNA as described herein) includes base pairing of the first nucleotide sequence over the entire length of one or two nucleotide sequences Nucleotide or polynucleotide and oligonucleotide or polynucleotide comprising a second nucleotide sequence. These sequences may be referred to herein as "fully complementary" to each other. However, if first in this context A sequence is said to be "substantially complementary" to a second sequence, and the two sequences may be fully complementary, or may form one or more when hybridizing up to a 30 base pair duplex, but generally does not exceed 5, 4 '3 or 2 mismatched base pairs while maintaining the ability to hybridize under conditions close to their final application', such as by RISC pathway-inhibiting genes. However, if two nucleotides are designed to form during hybridization One or more single-stranded overhangs' are complementary For the purposes of this determination, such pendants should not be considered mismatched. For example, for the purposes described herein, an oligonucleotide of 21 nucleotides in length and 23 nucleosides of another length are included. Acidic oligonucleotides' and duplexes in which the longer oligonucleotide comprises a 21 nucleotide sequence that is fully complementary to the shorter oligonucleotide may still be referred to as "completely complementary as described above" The overhang describes the unpaired nucleotide at the 3, or 5, end of the double-stranded nucleotide duplex. In one embodiment, the overhang is from 〇 to 4 nt long and is on the 3' end. The RNAi agent of the invention is complementary or substantially complementary to the target sequence in the target p_ENaC and is double-stranded, comprising a sense strand and an antisense strand (which may be continuous, loop-joined or joined), wherein the double-stranded region is 9 to 36 #长(especially for example 19·22 bp or 19-23 bp long), and in addition may optionally contain 3, or 5, overhangs, and the RNAi agent may additionally contain 3, cap end RNAi agent-mediated ruler 1 154740.doc -43- 201141489 Disturb, down-regulate or inhibit the content, performance and/or activity of β-ENaC, and/or establish or reconstruct a substantially normal course The ENaC and / or β-ENaC activity or other biological functions associated with the ENaC. RNAi agents that reduce p-ENaC content, performance and/or activity RNAi agents that are dry to β-ENaC include those that bind to the p_ENaC sequences provided herein and which are used to reduce β-ENaC via the RNAi mechanism. Exemplary siRNAs for p-ENaCi are provided, for example, in Table 1. The RNAi agent of the present invention silences, inhibits, down-regulates, and/or inhibits the expression of the β-ENaC gene by the β-ENaC gene such that substantially normal levels of β_ENaC activity, performance and/or content and/or Na+ resorption are achieved. Moreover, in various embodiments, depending on the disease condition and the biological environment, it is acceptable to use the RNAi agents of the present invention to establish β-ENaC performance, activity and/or content to a lesser extent than normal or above normal.

此項技術中已知之任何方法可用於量測由p_ENaC siRNA誘發之β-ENaC活性、含量及/或表現的改變。可在 多個時間點、投與siRNA之前、期間及之後進行量測以測 定siRNA之作用。 只要提及β-ENaC基因，本文之術語「沉默」、「抑制表 現」、下調表現」、「抑止表現」及其類似術語係指如可由 自第一細胞或細胞群分離或在其中偵測到之p_ENaC mRNA 的量降低所表現的至少部分抑止P_ENaC基因之表現，在該 細胞或細胞群中轉錄MNac基因且已經處理該細胞或細= 群使得相較於與第m細料實質-μ目同但未經處理 的第二細胞或細胞群（對照細胞）抑制p_ENaC基因之表現。 154740.doc 201141489 抑制程度一般根據下式表示 等式1 之mRNA)-(經處理細胞中之mRNA) (對照細胞中之mRN A) · ° 或者’抑制程度可根據與β-ENaC基因表現功能性相關 之參數的降低給出，例如β—ENaC基因編碼之蛋白質的量、 肺流體含量或黏液含量改變等。原則上，可在組成性或藉Any method known in the art can be used to measure changes in β-ENaC activity, content and/or performance induced by p_ENaC siRNA. Measurements can be performed before, during, and after administration of siRNA at various time points to determine the effect of siRNA. As far as the reference to the β-ENaC gene is concerned, the terms "silence", "inhibition of performance", "downregulation", "suppression of performance" and the like are used herein to mean, for example, being isolated from or detected in a first cell or cell population. A decrease in the amount of p_ENaC mRNA, at least in part, inhibits the expression of the P_ENaC gene, which transcribes the MNac gene in the cell or cell population and has treated the cell or the fine = group so that it is the same as the m-th substance However, the untreated second cell or cell population (control cells) inhibited the expression of the p_ENaC gene. 154740.doc 201141489 The degree of inhibition is generally expressed by the following formula: mRNA of Equation 1) (mRNA in treated cells) (mRN A in control cells) · ° or 'degree of inhibition can be expressed according to the function with β-ENaC gene The reduction in the relevant parameters gives, for example, the amount of protein encoded by the β-ENaC gene, changes in lung fluid content or mucus content, and the like. In principle, it can be constitutive or borrowed

由遺傳工程改造表現β-ENaC之任何細胞中且藉由任何適當 檢定測定β-ENaC基因沉默。然而，當需要參考或對照以測 定既定RNAi劑是否特定程度地抑制β-ENaC基因表現且因 此為本發明所涵蓋時，以下實例中提供之檢定將用作該參 考。 舉例而言，在特定情形中，藉由投與本發明之RNAi劑 將β-ENaC基因之表現抑止至少約10%、15%、20%、 25%、30%、35%、40%、45% 或 50%。在一些實施例中， 藉由投與本發明之RNAi劑將β-ENaC基因抑止至少約 60%、70%或80%。在一些實施例中，藉由投與本文所述 之RNAi劑將β-ENaC基因抑止至少約85%、90%、或95%或 95%以上。 首先可活體外測試RNAi劑抑止β-ENaC之能力（例如使用 測試細胞，諸如H441)。 接著可使用例如PBMC(周邊血液單核細胞）檢定測試可 活體外抑止β-ENaC之RNAi劑的免疫刺激。亦可在動物測 試中測試RNAi劑。測試及對照動物包括β-ENaC過表現或 不足表現之彼等’如例如Hummer等人，2005 J. Am. Soc. 154740.doc •45- 201141489The β-ENaC gene silencing is determined by genetic engineering of any cell expressing β-ENaC and by any suitable assay. However, when a reference or control is required to determine whether a given RNAi agent specifically inhibits the expression of the β-ENaC gene and is therefore covered by the present invention, the assay provided in the following examples will be used as such reference. For example, in certain instances, the performance of the β-ENaC gene is inhibited by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45 by administration of the RNAi agent of the present invention. % or 50%. In some embodiments, the β-ENaC gene is inhibited by at least about 60%, 70%, or 80% by administration of a RNAi agent of the invention. In some embodiments, the β-ENaC gene is inhibited by at least about 85%, 90%, or 95% or more by administering a RNAi agent as described herein. The ability of the RNAi agent to inhibit β-ENaC can first be tested in vitro (e. g., using test cells such as H441). Immunostimulation of RNAi agents that inhibit β-ENaC in vitro can then be tested using, for example, PBMC (peripheral blood mononuclear cells) assays. RNAi agents can also be tested in animal tests. Test and control animals include those whose beta-ENaC over or under performance is as 'for example, Hummer et al., 2005 J. Am. Soc. 154740.doc • 45- 201141489

Nephrol. 16: 3160-3166 ; Randrianarison等人，2007 Am. J. Physiol. Lung Cell. Mol· Physiol. 294: 409-416 ; Cao等人， 2006 Am. J. Physiol. Renal Physiol.及其中引用之參考案中 所述。抑止或改變β-ENaC之含量、活性及/或表現的RNAi 劑可用於治療多種β-ENaC相關疾病的藥物中。Nephrol. 16: 3160-3166; Randrianarison et al., 2007 Am. J. Physiol. Lung Cell. Mol· Physiol. 294: 409-416; Cao et al., 2006 Am. J. Physiol. Renal Physiol. Said in the reference. RNAi agents that inhibit or alter the content, activity, and/or performance of β-ENaC can be used in the treatment of a variety of β-ENaC-related diseases.

在β-ENaC或β-ENaC相關疾病之症狀的情形中，「降低」 意謂該含量之統計學上顯著降低❶降低可為例如至少 10%、至少20%、至少30%、至少40%或40%以上。若對於 特定疾病或罹患特定疾病之個體，β-ENaC之含量或表現升 高’則以本發明之β-ENaC RNAi劑治療可將β-ENaC之含量 或表現特疋降低至文獻中視為在未患該病症之個體的正常 範圍内的含量。可藉由評估mRNA(例如經北方墨點或 PCR)或蛋白質（例如西方墨點）量測p_ENaC之含量或表現。 可藉由量測β-ENaC基因轉錄速率（例如經北方墨點；或逆 轉錄酶聚合酶鏈反應或即時聚合酶鍵反應）測定RNAi劑對 β-ENaC表現之作用。RT-PCR已用於顯示p_ENaC之mRNA 含量在腎臟、胰臟及***中較高，且在肝臟及脾臟中含 量中等。Brauner-〇sb〇rne 等人，2〇〇1 Bi〇chim Bi〇physIn the case of a symptom of a β-ENaC or β-ENaC-related disease, "reduction" means a statistically significant decrease in the content, and the reduction may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or 40% or more. If the content or performance of β-ENaC is elevated for a specific disease or an individual suffering from a specific disease, treatment with the β-ENaC RNAi agent of the present invention can reduce the content or performance characteristic of β-ENaC to the literature as The amount within the normal range of an individual suffering from the condition. The amount or performance of p_ENaC can be measured by assessing mRNA (e.g., via northern blots or PCR) or proteins (e.g., western blots). The effect of the RNAi agent on the expression of β-ENaC can be determined by measuring the rate of transcription of the β-ENaC gene (e.g., via northern blots; or reverse transcriptase polymerase chain reaction or immediate polymerase bond reaction). RT-PCR has been shown to show that the mRNA content of p_ENaC is higher in the kidney, pancreas and prostate, and is moderately present in the liver and spleen. Brauner-〇sb〇rne et al., 2〇〇1 Bi〇chim Bi〇phys

Acta 15 18: 237-248。可例如藉由表現p_ENaC之組織的西 方墨點直接量測β-ENaC(由細胞表面表現）之含量。 如本文所用’「下調」係指P_ENaC之生物活性及/或表現 的任何統計學顯著降低，包括完全阻斷活性（亦即完全抑 制）及/或表現。舉例而言’「下調」可係指p_ENaC含量、 活性及/或表現降低至少約1〇、2〇、3〇、4〇、5〇、6〇、 154740.doc -46- 201141489 70、80、90或 100% 0Acta 15 18: 237-248. The amount of β-ENaC (expressed by the cell surface) can be directly measured, for example, by the western ink dot representing the tissue of p_ENaC. "down-regulation" as used herein refers to any statistically significant decrease in the biological activity and/or performance of P_ENaC, including complete blocking activity (i.e., complete inhibition) and/or performance. For example, 'downregulation' may mean a decrease in p_ENaC content, activity and/or performance of at least about 1〇, 2〇, 3〇, 4〇, 5〇, 6〇, 154740.doc -46- 201141489 70, 80, 90 or 100% 0

如本文所用，術語「抑制 R ”利」β-ENaC係指β-ENaC之生物 含量、活性及/或表現的任何統計學顯著降低，包括完全 阻斷活性及/或表現。舉例而言，「抑制」可係指β-ENaC含 量、活性及/或表現降低至少約1〇、2〇、3〇、4〇、5〇、 60、70、80、90或⑽％。如本文所用，在提及任何其他 生物試劑或組合物的同時’術語「抑制」類似地係指含 φ 量、活性及/或表現顯著降低。 「含量」意謂β-ENaC RNAi劑可改變p_ENaC之含量，例 如β-ENaC mRNA之含量或β-ENaC蛋白質之含量、或卜 ENaC之活性程度。 一些疾病（諸如囊腫性纖維化）特徵為過度ENaC介導之 Na+吸收。尤其在一實施例中，在特徵為p_ENaC過度表現 及/或高活性之疾病的情形中，投與針對p_ENaC之RNAi劑 可降低β-ENaC之含量、表現及/或活性。然而，p_ENaC^ • 含量過低亦可導致損害肺流體清除及腎功能障礙。As used herein, the term "inhibiting R" means "beta-ENaC" refers to any statistically significant decrease in the biological content, activity and/or performance of β-ENaC, including complete blocking activity and/or performance. For example, "inhibiting" may mean a decrease in the beta, ENaC content, activity and/or performance of at least about 1, 2, 3, 4, 5, 60, 70, 80, 90 or (10)%. As used herein, the term "inhibition" when referring to any other biological agent or composition similarly refers to a significant decrease in the amount, activity, and/or performance of φ. "Content" means that the β-ENaC RNAi agent can change the content of p_ENaC, such as the content of β-ENaC mRNA or the content of β-ENaC protein, or the degree of activity of ENaC. Some diseases, such as cystic fibrosis, are characterized by excessive ENaC-mediated Na+ absorption. In particular, in one embodiment, administration of a RNAi agent against p_ENaC reduces the amount, performance and/or activity of β-ENaC in the context of a disease characterized by overexpression and/or high activity of p_ENaC. However, too low p_ENaC^ • can also cause damage to lung fluid clearance and renal dysfunction.

Randrianarison 等人，2007 Am. J. Physiol· Lung Cell. Mol. Physiol. 294: 409-416。因此，在多個實施例中，投 與針對β-ENaC之RNAi劑尤其建立或重建正常或大致正常 程度之β-ENaC活性、表現及/或含量。 就含量 '表現及/或活性而言之「正常」或「大致正 常」意謂健康細胞、組織或器官中β-ENaC的含量、表現或 活性的至少：約50%、約60%、約70%、約80%、約9〇%及/ 或約100% ;及/或不超過：約100%、約120%、約130〇/〇、 154740.doc • 47 - 201141489 約140%或約1 50%。此可使用例如肺或腎組織勻漿量測， 如 Gambling等人，2004 Kidney Inti. 65: 1774-1781 中所述。 尤其在一實施例中，投與適當量之適當β-ENaC RNAi劑會 使β-ENaC含量、活性及/或表現及/或Na+再吸收程度恢復 至健康細胞、組織或器官的約50%至約150%、更特定言之 約60%至約140%、更特定言之約70%至約130%、更特定言 之約80°/。至約120%、更特定言之約90%至約110%、及最特 定言之約100%。β-ENaC活性程度亦可藉由肺流體平衡間 接量測。肺流體平衡可藉由計算貧血（bloodless)、肺濕乾 重量比（反映血管外肺水量）估算。Randrianarison等人， 2007 Am. J. Physiol. Lung Cell. Mol. Physiol. 294: 409-4 1 6。β-ENaC活性程度亦可藉由肺（尤其細支氣管、肺泡 管、肺泡上皮及血管）的組織學研究間接量測。 Randrianarison 等人，2007 ;及 Zhou 等人，2008 人111.】.1165卩· Crit. Care Med. 178: 1245-1256。向患有β-ENaC相關疾病 之患者投與β-ENaC RNAi因此會使β-ENaC之含量、活性及 /或表現及Na+再吸收程度特定恢復至大致正常程度，如直 接量測β-ENaC mRNA或蛋白質含量或間接測定（諸如分析 組織學樣品或肺流體含量）所測定。 此外，在多個實施例中，視疾病病況及生物環境而定， 可接受使用本發明之RNAi劑建立低於正常程度或高於正 常程度之程度的β-ENaC表現、活性及/或含量。 已知多種因子會改變ENaC或特定言之β-ENaC之含量。 提高ENaC之生理學活性的激素包括醛固酮、升壓素 154740.doc -48- 201141489 (vasopressin)及胰島素。β-EnaC因升壓素及水分限制、以 及在大鼠中竣酸氫納負載期間特定上調。此等多種因子可 用作測定RNAi劑對β-ENaC含量之作用的對照。 RNAi劑之類型及其修飾 此項技術中熟知使用包含反義核酸之RNAi劑或組合物 下調細胞中特定蛋白質之表現。RNAi劑包含與另一核酸 (例如mRNA)之編碼股互補且能夠與其氫鍵結合（hydr〇gen • binding)之序列。因此，在多個實施例中，本發明之RNAi 劑涵蓋靶向（例如互補、能夠氫鍵結合等）例如表1中提出之 任何序列的任何RN A i劑。 與mRNA互補之反義序列可與編碼區、之5'或3,未 轉譯區、及/或橋接編碼及未轉譯區之區、及/或其部分互 補。此外，RNAi劑或其部分可與編碼mRNA之基因的調節 區互補’例如轉錄或轉譯起始序列或調節元件。特定言 之’ RNAi劑或其部分可與在mRNA之編碼股上或3'未轉譯 • 區中的初始密碼子之前或跨接該初始密碼子之區互補。 RNAi劑分子可根據Watson及Crick驗基配對原則設計。 RNAi劑可與β-ENaC mRNA之整個編碼區互補，但更特定 言之為與β-ENaC mRNA之編碼或非編碼區之僅一部分反義 的募核苷酸。舉例而言，反義寡核苷酸可與β-ENaC mRNA 之轉譯起始位點周圍的區互補。反義寡核苷酸可為例如約 5、10、15、19、20、21、22、23、24、25、30、35、 40、45或50個核苷酸長。 RNAi劑可在一端或兩端具有内部修飾。末端之修都可 154740.doc 49· 201141489 幫助穩定RNAi劑，保護其免於被血液中之核酸酶降解。 RNAi劑可視情況針對已知或預測接近或處於基因剪接位 點處的β-ENaC mRNA之區；例如外顯子-内含子接合點（例 如Saxena等人，1998中所述）。 RNAi劑亦可視情況經設計以黏接於已知或預測的mRNA 之暴露及/或單股區（例如環）。 RNAi劑可使用化學合成及使用此項技術中已知之程序 的酶促接合反應構築。舉例而言，RNAi劑可使用天然存 在之核苷酸或以各種方式經修飾之核苷酸化學合成，該等 經修飾核苷酸經設計以降低脫靶作用、及/或提高分子之 生物穩定性或提高反義與有義核酸之間形成的雙鏈體之物 理穩定性’例如可使用硫代磷酸酯衍生物及吖啶取代之核 苷酸。 「G」、「Cj、「A」、「T」及「U」一般各自代表分別含 有鳥嘌呤、胞嘧啶、腺嘌呤、胸苷及尿嘧啶作為鹼基之核 苷酸。然而，術語「核糖核苷酸」或「核苷酸」亦可係指 經修飾核苷酸或代用置換部分。熟習此項技術者熟知鳥嗓 °令、胞啦啶、腺嘌呤及尿嘧啶可經其他部分置換，而不實 質上改變包含攜帶該置換部分之核苷酸之寡核苷酸的鹼基 配對特性《舉例而言（非限制性），包含肌苷作為其鹼基之 核普酸可與含有腺嘌呤、胞嘧啶或尿嘧啶之核苷酸鹼基配 對。因此’本發明之dsRNA的核苷酸序列中含有尿嘧啶、 鳥嗓吟或腺嘌呤之核苷酸可經含有例如肌苷之核苷酸置 換。在另一實例中，寡核苷酸任何位置處之腺嘌呤及胞喷 I54740.doc -50· 201141489 啶可分別置換為鳥嘌呤及尿嘧啶形成與目標mRNA配對之 G-U Wobble鹼基。含有該等置換部分之序列適於本發明之 組合物及方法。 熟練技術人員將瞭解術語「RNA分子」或「核糖核酸分 子」不僅涵蓋天然表現或發現（亦即天然存在）之rNa分 子，而且亦涵蓋RNA之非天然存在之類似物及衍生物，包 含如本文所述或如此項技術已知之一或多個核糖核苷酸/ • 核糖核苷類似物或衍生物。嚴格而言，「核糖核苷」包括 核苷鹼基及核糖，且「核糖核苷酸」為具有丨' 2或3個磷 酸酯部分之核苷。然而，如本文所用，術語「核糖核苷」 及「核糖核苷酸」可視為相同。RNA在核苷鹼基結構或磷 酸核糖骨架結構中可經修飾，例如如下文所述。然而，包 含核糖核苷類似物或衍生物之分子必需保持形成雙鏈體之 能力。作為非限制性實例，RNA分子亦可包括至少一個經 修飾核苷，包括（但不限於）經2，_〇_甲基修飾之核苷酸、包 • 含5’硫代磷酸酯基之核苷、與膽固醇基衍生物或月桂酸雙 癸基醯胺基連接之末端核苷、鎖定核苷、無鹼基核苷、經 2-去氧-2-氣修飾之核芽、經2，_胺基-修飾之核普、經2，_烷 基-修飾之核苷、N-嗎啉基核苷、未鎖定核糖核苷酸（例如 非環狀核苷酸單體，如w〇 2〇〇8/147824中所描述）、胺基 填酸酯或包含非天然驗基之核苦、或其任何組合。或者， RNA分子可包含至少2個、至少3個、至少4個、至少5個、 至少6個、至少7個、至少8個、至少9個、至少1〇個、至少 15個、至少20或20個以上j^dsRNA分子的整個長度的經 I54740.doc •51- 201141489 修飾核糖核苷。RNA分子中該複數個經修飾核糖核苷中每 一者的修飾無需相同。在一實施例中，預期用於本文所述 方法及組合物中之經修飾R N A為能夠形成所要雙鏈體結構 且允許或介導目標RNA經RISC路徑之特異性降解的肽核酸 (PNA) 〇 可用於產生RN A i劑之經修飾核苷酸之實例包括5 _氟尿嘧 啶、5-溴尿嘧啶、5_氣尿嘧啶' 5_碘尿嘧啶、次黃嘌呤、 月0示呤（xantine)、4-乙醯基胞嘧啶、5·(羧基羥基甲基）尿嘧 啶、5-羧基甲胺基甲基_2_硫尿苷、5_羧基甲胺基甲基尿嘧 咬、二氫尿嘴啶、β-D-半乳糖苷基q核苷（que〇sine)、肌 苦、N6-異戊烯基腺嘌呤、丨_甲基鳥嘌呤、丨_曱基肌苷、 2,2-二曱基鳥嘌呤、2_甲基腺嘌呤、2-甲基鳥嘌呤、3_甲 基胞嘧啶、5 -甲基胞嘧咬、N6-腺嘌呤、7-曱基鳥嘌呤、5-甲胺基甲基尿嘧啶、5-甲氧基胺基甲基_2·硫代尿嘧啶、 D-甘露糖基Q核苷、5，-甲氧基羧基甲基尿嘧啶、5_甲氧基 尿嘧啶、2-甲硫基-Ν6-異戊烯基腺嘌呤、尿嘧啶_5_氧基乙 酸（ν)、假尿苷（wybutoxosine)、假尿嘧啶、Q核苷、2-硫代 胞嘧啶、5-甲基-2-硫代尿嘧啶、2-硫代尿嘧啶、4-硫代尿 嘧啶、5-曱基尿嘧啶、尿嘧啶_5_氧基乙酸曱酯、尿嘧啶-5-氧基乙酸（ν)、5-甲基-2-硫代尿嘧啶、3-(3-胺基-3-N-2-羧基丙基）尿嘧啶、（acp3)w及2,6·二胺基嘌呤。 在一實施例中’本發明涵蓋本文揭示之任何RNAi劑的 任何經修飾變異體。經修飾變異體含有相同序列，但可經 修飾以含有磷酸酯、糖、鹼基、核苷酸等的修飾。舉例而 154740.doc •52· 201141489 S，經修飾變異體可含有本文所列之經修飾核苷酸中的一 或多者，例如C置換為2’-經修飾之C。 在一態樣中，經修飾核糖核苷包括去氧核糖核苷。在該 情形中，RNAi劑可包含一或多個去氧核苷，包括例如去 氧核苷懸垂物、或dsRNA雙股部分内之一或多個去氧核 苷。然而，不言而喻，任何情形中術語「RNAi劑」均不 涵蓋雙股DNA分子。 以去氧核糖核苷酸置換具有兩個核苷酸3，_懸垂物之2 j _ 聚合體siRNA雙鏈體的3’-末端核苦酸懸垂區段不會對RNAi 活性產生不良作用。已充分容許將siRNA之每一端的多達 四個核苷酸置換為去氧核糖核苷酸，而以去氧核糖核芽酸 完全取代導致無RNAi活性。國際pct公開案第w〇 00/44914號及Beach等人，國際pCt公開案第w〇 01/68836 號預先表明siRNA可包括對磷酸酯-糖骨架或核苷的修飾， 以納入至少一個氮或硫雜原子。Kreutzer等人，加拿大專 利申请案第2,359,180號亦描述用於dsRNA構築體之特定化 學改質，以抵消雙股RNA依賴性蛋白質激酶j>KR，特定言 之2’-胺基或2’-0-甲基核苷酸、及含有2'-〇或4'-C亞曱基橋 之核苷酸的活化。額外3’-末端核苷酸懸垂物包括dT(去氧 胸苷）、2’-0,4，-C-伸乙基胸苷（eT)及2-羥基乙基磷酸酯 (hp)。Randrianarison et al., 2007 Am. J. Physiol Lung Cell. Mol. Physiol. 294: 409-416. Thus, in various embodiments, administration of a RNAi agent against β-ENaC specifically establishes or regenerates normal or substantially normal levels of β-ENaC activity, performance and/or content. "Normal" or "substantially normal" in terms of content 'performance and/or activity means at least about 50%, about 60%, about 70% of the content, performance or activity of β-ENaC in healthy cells, tissues or organs. %, about 80%, about 9〇% and/or about 100%; and/or no more than: about 100%, about 120%, about 130〇/〇, 154740.doc • 47 - 201141489 about 140% or about 1 50%. This can be measured, for example, using lung or kidney tissue homogenates as described in Gambling et al., 2004 Kidney Inti. 65: 1774-1781. In particular, in an embodiment, administration of an appropriate amount of a suitable β-ENaC RNAi agent will restore the β-ENaC content, activity and/or performance and/or degree of Na+ resorption to about 50% of healthy cells, tissues or organs. About 150%, more specifically about 60% to about 140%, more specifically about 70% to about 130%, and more specifically about 80°/. To about 120%, more specifically about 90% to about 110%, and most preferably about 100%. The degree of β-ENaC activity can also be measured by indirect measurement of lung fluid balance. Lung fluid balance can be estimated by calculating the bloodless, lung wet weight ratio (reflecting extravascular lung water volume). Randrianarison et al, 2007 Am. J. Physiol. Lung Cell. Mol. Physiol. 294: 409-4 1 6. The degree of β-ENaC activity can also be measured indirectly by histological studies of the lungs, particularly bronchioles, alveolar ducts, alveolar epithelium, and blood vessels. Randrianarison et al., 2007; and Zhou et al., 2008, 111.]. 1165卩· Crit. Care Med. 178: 1245-1256. Administration of β-ENaC RNAi to patients with β-ENaC-related diseases therefore specifically restores beta-ENaC content, activity and/or performance and Na+ reabsorption to a substantially normal level, such as direct measurement of β-ENaC mRNA Or as determined by protein content or indirect assays (such as analysis of histological samples or lung fluid content). Moreover, in various embodiments, depending on the disease condition and the biological environment, it is acceptable to use the RNAi agents of the present invention to establish β-ENaC performance, activity and/or content to a lesser extent than normal or above normal. A variety of factors are known to alter the content of ENaC or specifically beta-ENaC. Hormones that increase the physiological activity of ENaC include aldosterone, vasopressin 154740.doc -48-201141489 (vasopressin) and insulin. β-EnaC is specifically up-regulated during vasopressin and water restriction, as well as during guanidine hydrochloride loading in rats. These various factors can be used as controls for determining the effect of RNAi agents on beta-ENaC levels. Types of RNAi Agents and Modifications It is well known in the art to use RNAi agents or compositions comprising antisense nucleic acids to downregulate the performance of a particular protein in a cell. A RNAi agent comprises a sequence that is complementary to a coding strand of another nucleic acid (e.g., mRNA) and capable of hydrogen bonding with it. Thus, in various embodiments, the RNAi agents of the invention encompass any RN Agent that is targeted (e.g., complementary, capable of hydrogen bonding, etc.), such as any of the sequences set forth in Table 1. The antisense sequence complementary to the mRNA may complement the coding region, 5' or 3, the untranslated region, and/or the region encoding the coding and untranslated region, and/or portions thereof. Furthermore, the RNAi agent or portion thereof may be complementary to a regulatory region of a gene encoding the mRNA' such as a transcriptional or translational initiation sequence or regulatory element. The particular 'RNAi agent or portion thereof can be complementary to the region preceding the initial codon in the coding strand of the mRNA or in the 3' untranslated region or across the initial codon. RNAi agent molecules can be designed according to the Watson and Crick test pairing principles. The RNAi agent may be complementary to the entire coding region of the β-ENaC mRNA, but more specifically to a nucleotide that is antisense to only a portion of the coding or non-coding region of the β-ENaC mRNA. For example, an antisense oligonucleotide can be complementary to a region surrounding the translation initiation site of β-ENaC mRNA. The antisense oligonucleotide can be, for example, about 5, 10, 15, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45 or 50 nucleotides in length. The RNAi agent can have internal modifications at one or both ends. The end of the repair can be 154740.doc 49· 201141489 Helps stabilize the RNAi agent and protect it from nuclease degradation in the blood. The RNAi agent can be directed to a region of β-ENaC mRNA that is known or predicted to be near or at a gene splice site; for example, an exon-intron junction (as described in Saxena et al., 1998). The RNAi agent can also be designed to adhere to known or predicted mRNA exposures and/or single-stranded regions (e.g., loops). RNAi agents can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, a RNAi agent can be chemically synthesized using naturally occurring nucleotides or modified nucleotides in a variety of ways designed to reduce off-target effects and/or enhance the biological stability of the molecule. Or to increase the physical stability of the duplex formed between the antisense and the sense nucleic acid', for example, a phosphorothioate derivative and an acridine-substituted nucleotide can be used. "G", "Cj, "A", "T" and "U" generally represent nucleotides containing guanine, cytosine, adenine, thymidine and uracil as bases, respectively. However, the term "ribonucleotide" or "nucleotide" may also refer to a modified nucleotide or a substituted moiety. It is well known to those skilled in the art that guanine, cytidine, adenine and uracil can be replaced by other moieties without substantially altering the base pairing properties of the oligonucleotide comprising the nucleotide carrying the replacement moiety. By way of example and not limitation, a nucleotide containing inosine as its base can be base paired with a nucleotide containing adenine, cytosine or uracil. Therefore, the nucleotide containing uracil, guanine or adenine in the nucleotide sequence of the dsRNA of the present invention can be substituted with a nucleotide containing, for example, inosine. In another example, adenine and cell spray I54740.doc -50· 201141489 pyridine at any position of the oligonucleotide can be replaced with a G-U Wobble base paired with guanine and uracil to the target mRNA, respectively. Sequences containing such replacement moieties are suitable for the compositions and methods of the invention. The skilled artisan will appreciate that the term "RNA molecule" or "ribonucleic acid molecule" encompasses not only naturally occurring or discovered (ie, naturally occurring) rNa molecules, but also non-naturally occurring analogs and derivatives of RNA, as herein One or more ribonucleotides/ • ribonucleoside analogs or derivatives are known from the art or such techniques. Strictly speaking, "ribonucleoside" includes nucleobases and ribose, and "ribonucleotides" are nucleosides having 丨' 2 or 3 phosphate moieties. However, as used herein, the terms "ribonucleoside" and "ribonucleotide" may be considered the same. The RNA may be modified in a nucleobase structure or a phosphorose ribose backbone structure, for example as described below. However, molecules containing ribonucleoside analogs or derivatives must retain the ability to form duplexes. As a non-limiting example, the RNA molecule may also include at least one modified nucleoside including, but not limited to, a 2,_〇-methyl modified nucleotide, a package containing a 5' phosphorothioate group Glycosides, terminal nucleosides linked to cholesteryl derivatives or bismuthyl guanyl amide groups, locked nucleosides, abasic nucleosides, 2-deoxy-2-gas modified nuclear buds, 2,_ Amine-modified nucleosides, 2,-alkyl-modified nucleosides, N-morpholinyl nucleosides, unlocked ribonucleotides (eg, acyclic nucleomonomers such as w〇2〇) (Ath. 8/147,824), an amine-based acid ester or a nuclear bitter comprising a non-natural test group, or any combination thereof. Alternatively, the RNA molecule can comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 1, at least 15, at least 20 or The entire length of more than 20 j^dsRNA molecules was modified by I54740.doc • 51- 201141489 ribonucleosides. The modification of each of the plurality of modified ribonucleosides in the RNA molecule need not be the same. In one embodiment, the modified RNA contemplated for use in the methods and compositions described herein is a peptide nucleic acid (PNA) that is capable of forming the desired duplex structure and allowing or mediating specific degradation of the target RNA via the RISC pathway. Examples of modified nucleotides that can be used to produce the RN A i agent include 5-fluorouracil, 5-bromouracil, 5-oxyuracil '5-iodouracil, hypoxanthine, xantine, xantine, 4-Ethyl cytosine, 5 (carboxyhydroxymethyl) uracil, 5-carboxymethylaminomethyl 2- thiouridine, 5-carboxymethylamino uridine, dihydro urinal Pyridinium, β-D-galactoside q-nucleoside (que〇sine), muscle bitter, N6-isopentenyl adenine, 丨_methylguanine, 丨_merinosine, 2,2-di Indole guanine, 2-methyl adenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-mercaptoguanine, 5-methylamine Methyluracil, 5-methoxyaminomethyl-2-thiouracil, D-mannosyl Q nucleoside, 5,-methoxycarboxymethyluracil, 5-methoxyuridine Pyrimidine, 2-methylthio-purine 6-isopentenyl adenine, uracil 5_oxyacetic acid (ν), pseudouridine (wybutoxosine), pseudouracil, Q nucleoside, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-mercaptouracil, uracil-5-oxyacetate, uracil-5-oxyacetic acid (ν), 5-methyl-2-thiouracil, 3 -(3-Amino-3-N-2-carboxypropyl)uracil, (acp3)w and 2,6.diaminoguanidine. In one embodiment, the invention encompasses any modified variant of any of the RNAi agents disclosed herein. The modified variants contain the same sequence, but may be modified to contain modifications of phosphates, sugars, bases, nucleotides, and the like. For example, 154740.doc • 52· 201141489 S, the modified variant may contain one or more of the modified nucleotides listed herein, for example, C is replaced by 2'-modified C. In one aspect, the modified ribonucleoside comprises a deoxyribonucleoside. In this case, the RNAi agent may comprise one or more deoxynucleosides, including, for example, a deoxynucleoside suspension, or one or more deoxynucleosides within the double strand portion of the dsRNA. However, it goes without saying that the term "RNAi agent" does not encompass a double-stranded DNA molecule in any case. Replacement of the 3'-terminal nucleotide acid overhanging segment of a 2j-polymer siRNA duplex having two nucleotides 3, a dangling with deoxyribonucleotides does not adversely affect RNAi activity. It has been well tolerated to replace up to four nucleotides at each end of the siRNA with deoxyribonucleotides, while complete substitution with deoxyribose ribo-acid results in no RNAi activity. International PCT Publication No. W/00/44914 and Beach et al., International PCt Publication No. WO 01/68836 presuppose that siRNA may include modifications to a phosphate-sugar backbone or nucleoside to incorporate at least one nitrogen or Sulfur hetero atom. Kreutzer et al., Canadian Patent Application No. 2,359,180, also describes specific chemical modifications for dsRNA constructs to counteract double-stranded RNA-dependent protein kinases j>KR, specifically 2'-amino or 2'-0 - Activation of methyl nucleotides, and nucleotides containing a 2'-〇 or 4'-C fluorenylene bridge. Additional 3'-terminal nucleotide overhangs include dT (deoxythymidine), 2'-0,4,-C-extended ethylthymidine (eT) and 2-hydroxyethyl phosphate (hp).

Parrish等人，2000 Molecular Cell 6·· 1077-1087使用長 (>25 nt)siRNA 轉錄物測试 向線蟲（c. elegans)中之 unc-22 基因的特定化學改質。作者描述藉由將硫代磷酸酯核苷酸 154740.doc •53· 201141489 類似物與T7及T3 RNA聚合酶合併將硫代磷酸酯殘基引入 至此等siRNA轉錄物中’且觀測到具有兩個硫代碳酸酯修 飾之鹼基的RNA亦具有如RNAi之效用實質降低。此外， Parrish等人報導兩個以上殘基之硫代磷酸酯修飾活體外使 RNA很大程度上不穩定，使得不能檢定干擾活性。同前 1081頁。作者亦測試長siRNA轉錄物中之核苷酸糖2'-位置 的特定修飾，且發現以去氧核苷酸取代核糖核苷酸引起干 擾活性實質降低’在尿苷取代為胸苷及/或胞苷取代為去 氧胞苷的情形中尤其如此。同前。此外，作者測試特定鹼 基修飾，包括在siRNA之有義股及反義股中以4-硫代尿嘧 啶、5-溴尿嘧啶、5-碘尿嘧啶及3-(胺基烯丙基）尿嘧啶取 代尿嘧啶，及以肌苷取代鳥苷。而看似容許4-硫代尿嘧啶 及5-溴尿〇密咬取代，parrish報導肌苷在併入任一股中時引 起干擾活性實質降低。Parrish亦報導在反義股中併入5-硬 尿嘧啶及3-(胺基烯丙基）尿嘧啶亦導致RNAi活性實質降 低。 熟習此項技術者應瞭解可能使用此項技術中已知之任何 習知方法根據需要合成及修飾siRNA(參看Henschel等人， 2004 DEQOR： a web-based tool for the design and quality control of siRNAs. Nucleic Acids Research 32 (Web Server Issue): W113-W120)。此外，熟習此項技術者顯而易知， 存在適用於反義寡核苷酸、siRNA或shRNA表現構築體/載 體之多種調節序列（例如組成性或誘導性啟動子、組織特 異性啟動子或其功能性片段等）。 154740.doc -54- 201141489 此項技術中存在若干描述糖、鹼基、磷酸酯及骨架修飾 之實例’其可引入至核酸分子中以顯著提高其核酸酶穩定 性及功效。舉例而言’寡核苷酸經修飾以藉由以核酸酶抗 性基團修飾（例如2，-胺基、2，-C·烯丙基、2，-氟、2，-0-甲 基、2’-0-稀丙基、2’_H、核苷酸鹼基修飾）提高穩定性及/ 或提面生物活性（評論參看Usman及cedergren 1992 TIBS. 17. 34 ’ Usman 專人，1994 Nucleic Acids Symp. Ser. 31: 163，Burgin等人，1996 Bi〇cheinistry 35: 14090)。此項技 術中詳盡描述核酸分子之糖修飾。 已描述RNAi劑之其他修飾及結合。s〇utschek等人，2004 Nature 432: 173-178提出藉助於吡咯啶連接子使膽固醇與 siRNA分子之有義股的3,端結合，藉此產生共價且不可逆 結合。亦可對RNAi劑進行化學改質（包括與其他分子結合） 以增加活體内藥物動力學滞留時間及效率。 在多個實施例中，針對β-ENaC之RNAi劑包含：至少一 個51-尿苷-腺嘌呤_3’（5l_ua_3，）二核苷酸，其中尿苷為2，經 修飾核苷酸；至少一個5，_尿苷-鳥嘌呤_3,(5，_ug_3,)二核苷 酸，其中5’-尿苷為2’·經修飾核苷酸；至少一個5，_胞苷-腺 嘌呤-3’（5’-ca-3’）二核苷酸，其中5，_胞苷為2，_經修飾核苷 酸；及/或至少一個5，-尿苷-尿苦_3，（5，_uu_3，）二核苷酸，其 中5'-尿苷為2，-經修飾核苷酸。 在多個實施例中，RNAi劑包含選自由以下組成之群的 2'-修飾：2’-去氧、2’-去氧·2·-氟、2，_〇·曱基、2，_〇_甲氧基 乙基（2’-0-Μ0Ε)、2’-〇-胺基丙基（2·_〇_αρ)、2,_〇 二甲胺 154740.doc •55- 201141489 基乙基（2，-0-DMA0E)、2，-〇·二曱胺基丙基（2，_〇_DMAp)、 2’-0-二甲胺基乙氧基乙基（2’-〇-DMAEOE)及2，-〇-N-甲基 乙醯胺基（2·-0-ΝΜΑ)。 在另一實施例中’ RNAi包含間隙或缺失鹼基。舉例而 言，可存在磷酸酯-糖骨架，但鹼基缺失。 在另一實施例中’ RNAi劑具有單股切口（例如骨架中鍵 斷裂或缺失）。在多個實施例中’單股切口可在有義股或 反義股或其兩者中。 此切口可例如在有義股中，產生小内部分段干擾RN A或 sisiRNA ’其脫把作用可小於無切口之相應RNAi劑。 反義核酸或RNAi劑亦可具有替代骨架，諸如鎖定核酸 (LNA)、N-嗎啉基、肽核酸（pNA)、蘇糖核酸（TNA)或二醇 核酸（GNA)，及/或其可經標記（例如放射性標記或加標 籤）。 一股或兩股可包含替代骨架。 在另一實施例中’本發明方法採用之RNAi劑可包括α-異 頭核酸分子。a-異頭核酸分子與互補RNA(其中與一般卜單 兀相反’各股彼此平行）形成特異性雙股雜交物。Gauhier 等人.1987 Nucleic Acids. Res. 15: 6625-6641。 反義核酸分子亦可包含2，-鄰·甲基核糖核苷酸（In〇ue等 人，1987 Nucleic Acids Res. 15: 6131·6148)或嵌合RNA_ DNA 類似物（Inoue 等人，1987 FEBS Leu 215: 327 33〇)。 在另一實施例中，RNAi劑為核糖酶。核糖酶為具有核 糖核酸酶活性之催化性RNA分子，其能夠裂解與其具有互 154740.doc -56· 201141489 補區之單股核酸（諸如mRNA)。因此，核糖酶[例如錘頭狀 核糖酶（描述於 Haselhoff 等人，1988，Nature 334: 585-591 中)]可用於催化裂解β-ENaC mRNA轉錄物，藉此抑制β· ENaC mRNA之轉譯。 或者’可藉由乾向與β-ENaC之調節區（例如啟動子及/或 強化子）互補之核苷酸序列形成防止β-ENaC基因轉錄的三 螺旋結構來抑制基因表現。一般參看Helene 1991Parrish et al., 2000 Molecular Cell 6·1077-1087 used a long (>25 nt) siRNA transcript to test specific chemical modifications of the unc-22 gene in C. elegans. The authors describe the introduction of phosphorothioate residues into these siRNA transcripts by combining the phosphorothioate nucleotide 154740.doc •53·201141489 analog with T7 and T3 RNA polymerase' and observed to have two The RNA of the thiocarbonate modified base also has a substantial decrease in the utility of RNAi. Furthermore, Parrish et al. reported that phosphorothioate modification of two or more residues in vitro made the RNA largely unstable, making it impossible to characterize interference activity. Same as before 1081. The authors also tested specific modifications of the 2'-position of nucleotide sugars in long siRNA transcripts and found that substitution of ribonucleotides with deoxynucleotides resulted in a substantial decrease in interfering activity 'in uridine substitution to thymidine and/or This is especially the case when cytidine is substituted for deoxycytidine. Cit. In addition, the authors tested specific base modifications, including 4-thiouracil, 5-bromouracil, 5-iodouracil, and 3-(aminoallyl) in the sense and antisense strands of siRNA. Uracil replaces uracil and guanosine is replaced by inosine. While appearing to allow substitution of 4-thiouracil and 5-bromouridine, the parrish reported that inosine was substantially reduced in interference activity when incorporated into either strand. Parrish also reported that the incorporation of 5-hard uracil and 3-(aminoallyl)uracil in the antisense strand also resulted in a substantial decrease in RNAi activity. Those skilled in the art will appreciate that siRNA may be synthesized and modified as desired using any of the conventional methods known in the art (see Henschel et al, 2004 DEQOR: a web-based tool for the design and quality control of siRNAs. Nucleic Acids Research 32 (Web Server Issue): W113-W120). In addition, it will be apparent to those skilled in the art that there are a variety of regulatory sequences (eg, constitutive or inducible promoters, tissue-specific promoters or suitable for use in antisense oligonucleotides, siRNA or shRNA expression constructs/vectors) Its functional fragments, etc.). 154740.doc -54- 201141489 There are several examples in the art that describe sugars, bases, phosphates, and backbone modifications that can be introduced into nucleic acid molecules to significantly increase their nuclease stability and efficacy. For example, an oligonucleotide is modified to be modified with a nuclease resistant group (eg, 2,-amino, 2,-C-allyl, 2,-fluoro, 2,-0-methyl) , 2'-0-propyl, 2'-H, nucleotide base modification) to improve stability and / or bioactivity of the face (for review, see Usman and cedergren 1992 TIBS. 17. 34 ' Usman, 1994 Nucleic Acids Symp. Ser. 31: 163, Burgin et al., 1996 Bi〇cheinistry 35: 14090). The sugar modification of nucleic acid molecules is described in detail in this technique. Other modifications and combinations of RNAi agents have been described. S〇utschek et al., 2004 Nature 432: 173-178 proposes the binding of cholesterol to the 3' end of the sense strand of the siRNA molecule by means of a pyrrolidine linker, thereby producing a covalent and irreversible binding. RNAi agents can also be chemically modified (including binding to other molecules) to increase the residence time and efficiency of pharmacokinetics in vivo. In various embodiments, the RNAi agent for β-ENaC comprises: at least one 51-uridine-adenine_3' (5l_ua_3,) dinucleotide, wherein the uridine is 2, a modified nucleotide; a 5,_uridine-guanine_3, (5, _ug_3,) dinucleotide, wherein 5'-uridine is 2'-modified nucleotide; at least one 5,-cytidine-adenine- 3' (5'-ca-3') dinucleotide, wherein 5, _ cytidine is 2, _ modified nucleotide; and / or at least one 5, - uridine - urinary _ 3, (5 , _uu_3,) a dinucleotide in which the 5'-uridine is a 2,-modified nucleotide. In various embodiments, the RNAi agent comprises a 2'-modification selected from the group consisting of: 2'-deoxy, 2'-deoxy-2'-fluoro, 2, 〇 曱 、, 2, _ 〇_methoxyethyl (2'-0-Μ0Ε), 2'-〇-aminopropyl (2·_〇_αρ), 2,_〇 dimethylamine 154740.doc •55- 201141489 Base (2,-0-DMA0E), 2,-〇-diamidopropyl (2,_〇_DMAp), 2'-0-dimethylaminoethoxyethyl (2'-〇- DMAEOE) and 2,-〇-N-methylethylamino group (2·-0-ΝΜΑ). In another embodiment 'RNAi comprises a gap or a deleted base. For example, a phosphate-sugar backbone can exist, but bases are deleted. In another embodiment the 'RNAi agent has a single strand of nick (e.g., a bond break or deletion in the backbone). In various embodiments, a single strand cut can be in a sense strand or an antisense strand or both. This nick may, for example, in the sense strand, produce a small internal segmentation that interferes with RN A or sisiRNA', which may be less than the corresponding RNAi agent without the nick. The antisense nucleic acid or RNAi agent may also have an alternative backbone, such as a locked nucleic acid (LNA), N-morpholinyl, peptide nucleic acid (pNA), threose nucleic acid (TNA) or glycol nucleic acid (GNA), and/or it may Labeled (eg radiolabeled or tagged). One or two strands may contain an alternative skeleton. In another embodiment, the RNAi agent employed in the methods of the invention may comprise an alpha-anomeric nucleic acid molecule. The a-anomeric nucleic acid molecule forms a specific double-stranded hybrid with complementary RNA (in which the strands are parallel to each other). Gauhier et al. 1987 Nucleic Acids. Res. 15: 6625-6641. Antisense nucleic acid molecules may also comprise 2,-o-methyl ribonucleotides (In〇ue et al., 1987 Nucleic Acids Res. 15: 6131·6148) or chimeric RNA_DNA analogs (Inoue et al., 1987 FEBS) Leu 215: 327 33〇). In another embodiment, the RNAi agent is a ribozyme. A ribozyme is a catalytic RNA molecule having ribonuclease activity that is capable of cleaving a single-stranded nucleic acid (such as an mRNA) with which it has a complementary region to 154740.doc - 56 · 201141489. Thus, ribozymes [e.g., hammerhead ribozymes (described in Haselhoff et al., 1988, Nature 334: 585-591)] can be used to catalyze the cleavage of β-ENaC mRNA transcripts, thereby inhibiting translation of β·ENaC mRNA. Alternatively, gene expression can be inhibited by a nucleotide sequence complementary to a regulatory region of β-ENaC (e.g., a promoter and/or a enhancer) to form a triple helix structure that prevents transcription of the β-ENaC gene. See generally Helene 1991

Anticancer Drug Des· 6(6): 569-84 ; Helene等人，1992 Ann. N.Y. Acad. Sci. 660: 27-36 ;及 Maher 1992，Bioassays 14(12): 807-15 。 製造RNAi劑 可使用已以反義方向次選殖核酸之表現載體（亦即自插 入之核酸轉錄之RNA將處於所關注目標核酸的反義方向 上）以生物學方式製造RNAi劑。RNAi劑亦可使用以shRN A 構築體形式次選殖核酸之表現載體（亦即自***之核酸轉 錄之RNA將具有與所關注目標核酸反義方向的第一區、包 含環或鉸鏈之第二區、及與所關注目標核酸有義方向之第 三區’其中轉錄物之第一區及第三區較佳自身雜交，藉此 形成主幹-環結構）以生物學方式製造。 製造RNAi劑之方法為此項技術中所熟知且可為一般技 術人員獲得。 用於合成RNAi之套組自例如New England Biolabs及 Ambion市售購得。 傳遞RNAi劑 154740.doc 57- 201141489 本發明之RNAi劑可藉由此項技術中已知之任何方式傳 遞或引入（例如引入至活體外細胞、測試動物或人類中）。 本發明之RNAi劑通常向個體投與或原位產生，使得其 與編碼β-ENaC之細胞mRNA及/或基因組DNA雜交，且藉 由抑制轉錄及/或轉譯來抑制表現。RNAi劑之投與途徑的 實例包括在組織部位直接注射。或者，RNAi劑可經修飾 以靶向所選細胞，接著全身投與。舉例而言，對於全身投 與’反義分子可經修飾’使得其特異性結合於表現於所選 細胞表面上之受體或抗原，例如藉由連接反義核酸分子與 結合於細胞表面受體或抗原之肽或抗體。反義核酸分子亦 可使用此項技術中熟知且描述於例如US20070111230(其全 部内谷以引用的方式併入本文中）的載體傳遞至細胞。為 了實現反義分子的充分胞内濃度，反義核酸分子置於強 P〇l II或pol III啟動子控制下的載體構築體較佳。 如熟習此項技術者所瞭解，「引入至細胞中」在提及 RNAi劑時意謂促進或實現攝取或吸收至細胞中。藉由獨 立擴散（unaided diffusive)或主動細胞過程或藉由助劑或裝 置可發生RNAi劑的吸收或攝取。此術語之含義不限於活 體外細胞；RNAi劑亦可「引入至細胞中」，其中細胞為活 生物體的一部分。在該情形中，引入至細胞中將包括傳遞 至生物體。舉例而言’對於活體内傳遞而言，RNAi劑可 注射至組織部位中或可全身投與。亦可藉由β_葡聚糖傳遞 系統活體内傳遞’諸如美國專利第5,032,401號及第 5,607,677號、及美國公開案第2005/0281781號中所述之系 154740.doc -58- 201141489 統。活體外引入至細胞中包括此項技術中已知之方法，諸 如電穿孔及脂質體轉染。其他方法描述於本文中或為此項 技術中所知。 將RNAi劑傳遞至組織是一個難題，因為物質必需到達 目標器官且亦必需進入目標細胞之細胞質。RNA不能穿透 細胞膜，因此全身傳遞裸RNAi劑不可能成功。RNA被血 清中之RNAse活性迅速降解。出於此等原因，已設計將 RNAi劑傳遞至目標細胞的其他機制。此項技術中已知之 方法包括（但不限於）：病毒傳遞（反轉錄病毒、腺病毒、慢 病毒、桿狀病毒、AAV);脂質體（脂染胺、陽離子 DOTAP、中性DOPC)或奈米粒子（陽離子聚合物，pEI)、細 菌傳遞（tkRNAi)、及亦化學改質（LNA)siRNA以改良穩定 性。Xia 專人，2〇〇2 Nat. Biotechnol. 20及 Devroe 等人 2002. BMC Biotechnol. 2 1: 15揭示將siRNA併入至病毒載 體中。涵蓋用於傳遞RNAi劑之其他系統且本發明之RNAi 劑可藉由FDA或其他管理局發現及批准的多種方法傳遞。 本發明之RNAi劑可在適合醫藥組合物中傳遞。 RNAi劑之醫藥組合物 如本文所用，「醫藥組合物」包含醫藥有效量之一或多 種P-ENaC RNAi劑、醫藥學上可接受之載劑及與RNAi劑一 起協同作用之視情況選用之額外疾病治療。如本文所用， 「藥理學有效量」、「治療有效量」或僅「有效量」係指有 效產生所欲藥理學、治療或預防結果之RNAi劑的量。舉 例而5，若與疾病或病症有關之可量測參數存在至少1 〇% 154740.doc •59- 201141489 減少時認為既定臨床治療有效，則治療彼疾病或病症之藥 物的治療有效量為實現彼參數至少丨〇%減少所需之量。在 此實施例中，治療有效量之靶向P_ENaC的RNAi劑可將卜 ENaC蛋自質含量降低至少贈”在其他實施例中，當與疾 病或病症有關之可量測參數降低至少15、2〇、25、3〇、 35、40、45、50、55、60、65、70、75、80、85、90 或 95%時認為既定臨床治療有效’且用於；台療彼疾病或病症 之藥物的治療有效量為分別使彼參數降低至少15、2〇、 25、30、35、40、45、5〇、55、6〇、65、7〇、75、8〇、 85、90或95%的量。 術語「醫藥學上可接受之載劑」係指用於投與治療劑之 載劑。該等載劑包括（但不限於）生理食鹽水、緩衝鹽水、 右旋糖、m乙醇及其組合。該術語特定包括細胞 培養基。對於經口投與之藥物而言，t藥學上可接受之載 劑包括（但不限於）醫藥學上可接受之賦形劑’諸如惰性稀 釋劑、崩解劑、黏合劑、潤滑劑、甜味劑、調味劑、著色 劑及防腐劑。合適惰性稀釋劑包括碳酸鈉及碳酸鈣、磷酸 鈉及填酸弼，及乳糖m殿粉及褐藻酸為合適崩^ 劑。黏合劑可包括澱粉及明膠，而潤滑劑（若存在）一般將 為硬脂酸鎮、硬脂酸或滑石。^需要，則㈣可經諸如單 硬脂酸甘油酯或二硬脂酸甘油酯之物質包衣以延遲在胃腸 道中的吸收。本文進一步描述藥物調配物中包括之試劑。 包含β-ENaC RNAi劑之醫藥組合物可為固體形式，例如 散劑、顆粒、鍵劑、丸劑、囊形片（gelcap)、明膠膠囊、 154740.doc -60 · 201141489 脂質體、栓劑、可咀嚼形式或貼片。包含β_ΕΝ&跳嘣 之醫藥組合物亦可呈液體形式，例如溶液、乳液、懸浮 液、酏劑或糖漿。適當液體載劑可為例如水、有機溶劑， 諸如多元醇，諸如甘油或二醇’包括丙二醇及聚乙二醇， 或乙醇，Cremophor EL或其於水中之不同比例之混合物。 組合物可包含以白蛋白或界面活性劑塗覆的奈米尺寸之非 晶形或結晶顆粒。 • 適當載劑可包括例如抗菌劑及抗真菌劑、緩衝劑、碟酸 鈣、纖維素、甲基纖維素、氯丁醇、可可脂、著色劑、糊 精、乳化劑、腸溶塗膜、調味劑、明膠、等張劑、卵磷 脂、硬脂酸鎂、加香劑、多元醇（諸如甘露糖醇）、可注射 有機醋（諸如油酸乙酯、對羥基苯甲酸酯、笨紛山梨酸 (phenol sorbic acid)、聚乙二醇、聚乙烯吡咯啶、填酸鹽 緩衝鹽水（PBS)、防腐劑、丙二醇、羧甲基纖維素鈉、氣 化鈉、山梨糖醇、多種糖（包括（但不限於）蔗糖、果糖、半 籲 乳糖、乳糖及海藻糖）、澱粉、拴劑蠟、滑石、植物油（諸 如橄欖油及玉米油）、維生素、蠟及/或濕潤劑。對於卜 ENaC RNAi劑，較佳載劑包含聚葡萄糖及水，例如含5%右 旋糖之水（D5W)。 醫藥組合物之生物學惰性部分可視情況易蝕、允許定時 釋放RNAi劑》 醫藥組合物可包含幫助傳遞、穩定性、功效或降低免疫 原性之其他組分。 包含針對P-ENaC之RNAi劑的醫藥組合物 154740.doc -61 - 201141489 可添加包含針對β-ENaC之RNAi劑的醫藥組合物之其他 組分以幫助傳遞、穩定性、功效或降低免疫原性。 先前已使用脂質體進行藥物傳遞（例如傳遞化學治療 劑）。脂質體（例如陽離子脂質體）描述於PCT公開案 W002/100435A1、W003/015757A1 及 WO04029213A2 ;美 國專利第 5,962,016 號；第 5,030,453 號；及第 6,680,068 號；及美國專利申請案2004/0208921中。製造脂質體之方 法亦描述於W004/002453A1中。此外，中性脂質已併入至 陽離子脂質體中（例如Farhood等人，1995)。 陽離子脂質體已用於向多個細胞類型傳遞RNAi劑（Sioud 及 Sorensen 2003 ;美國專利申請案 2004/0204377 ; Duxbury 等人，2004 ; Donze 及 Picard，2002)。 中性脂質體之使用揭示於Miller等人，1998及美國專利申 請案 2003/0012812 中。 如本文所用，術語「SNALP」係指穩定的核酸脂質粒 子》SNALP表示塗覆減少之水相内核（包含核酸，諸如 iRNA或轉錄iRNA之質體）的脂質微囊。SNALP描述於例如 美國專利申請公開案第20060240093號、第20070135372號 及國際申請案第WO 2009082817號中。Anticancer Drug Des. 6(6): 569-84; Helene et al, 1992 Ann. N.Y. Acad. Sci. 660: 27-36; and Maher 1992, Bioassays 14(12): 807-15. Production of RNAi Agents RNAi agents can be biologically produced using expression vectors that have been subcloned in the antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be in the antisense orientation of the nucleic acid of interest). The RNAi agent may also use a expression vector for subcloning nucleic acid in the form of a shRN A construct (ie, the RNA transcribed from the inserted nucleic acid will have a first region in the antisense orientation to the target nucleic acid of interest, a second comprising a loop or a hinge The region, and the third region in which the target nucleic acid of interest is in the sense direction, wherein the first region and the third region of the transcript are preferably self-hybridized, thereby forming a backbone-loop structure, are biologically produced. Methods of making RNAi agents are well known in the art and are available to one of ordinary skill. Kits for the synthesis of RNAi are commercially available, for example, from New England Biolabs and Ambion. Delivery of RNAi Agents 154740.doc 57- 201141489 The RNAi agents of the invention can be delivered or introduced (e.g., introduced into ex vivo cells, test animals or humans) by any means known in the art. The RNAi agents of the present invention are typically administered to an individual or produced in situ such that they hybridize to cellular mRNA and/or genomic DNA encoding β-ENaC and inhibit expression by inhibiting transcription and/or translation. Examples of routes of administration of RNAi agents include direct injection at the tissue site. Alternatively, the RNAi agent can be modified to target the selected cells, followed by systemic administration. For example, for systemic administration of an 'antisense molecule can be modified' such that it specifically binds to a receptor or antigen present on the surface of a selected cell, for example by ligation of an antisense nucleic acid molecule to a cell surface receptor Or a peptide or antibody of an antigen. Antisense nucleic acid molecules can also be delivered to cells using vectors well known in the art and described, for example, in US20070111230, the entire entire disclosure of which is incorporated herein by reference. In order to achieve sufficient intracellular concentration of the antisense molecule, it is preferred that the antisense nucleic acid molecule is placed under the control of a strong P〇l II or pol III promoter. As is known to those skilled in the art, "introduction into a cell" when referring to a RNAi agent means promoting or achieving uptake or uptake into a cell. Absorption or uptake of the RNAi agent can occur by unaided diffusive or active cellular processes or by adjuvants or devices. The meaning of this term is not limited to in vitro cells; RNAi agents can also be "introduced into cells" where the cells are part of a living organism. In this case, introduction into the cell will include delivery to the organism. For example, for in vivo delivery, the RNAi agent can be injected into a tissue site or can be administered systemically. The system of 154740.doc-58-201141489, as described in U.S. Patent Nos. 5,032,401 and 5,607,677, and U.S. Patent Publication No. 2005/0281781, may also be incorporated by reference. Introduction into cells in vitro includes methods known in the art, such as electroporation and lipofection. Other methods are described herein or are known in the art. Delivery of a RNAi agent to a tissue is a problem because the substance must reach the target organ and must also enter the cytoplasm of the target cell. RNA does not penetrate the cell membrane, so systemic delivery of naked RNAi agents is unlikely to succeed. RNA is rapidly degraded by RNAse activity in serum. For these reasons, other mechanisms have been devised to deliver RNAi agents to target cells. Methods known in the art include, but are not limited to, viral delivery (retrovirus, adenovirus, lentivirus, baculovirus, AAV); liposomes (lipidamine, cationic DOTAP, neutral DOPC) or nai Rice particles (cationic polymer, pEI), bacterial delivery (tkRNAi), and also chemically modified (LNA) siRNA to improve stability. Xia, 2, 2 Nat. Biotechnol. 20 and Devroe et al. 2002. BMC Biotechnol. 2 1:15 reveals the incorporation of siRNA into viral vectors. Other systems for delivery of RNAi agents are contemplated and the RNAi agents of the invention can be delivered by a variety of methods discovered and approved by the FDA or other authorities. The RNAi agents of the invention can be delivered in a suitable pharmaceutical composition. Pharmaceutical Composition of a RNAi Agent As used herein, a "pharmaceutical composition" comprises a pharmaceutically effective amount of one or more P-ENaC RNAi agents, a pharmaceutically acceptable carrier, and an additional synergistic effect with the RNAi agent. Disease treatment. As used herein, "pharmacologically effective amount", "therapeutically effective amount" or "effective amount" alone refers to the amount of RNAi agent that is effective in producing the desired pharmacological, therapeutic or prophylactic result. For example, 5, if there is at least 1 〇% of the measurable parameters associated with the disease or condition 154740.doc •59- 201141489 When the reduction is considered to be effective for a given clinical treatment, the therapeutically effective amount of the drug for treating the disease or condition is to achieve The parameter is reduced by at least 丨〇%. In this embodiment, a therapeutically effective amount of a RNAi agent that targets P_ENaC can reduce the autologous content of the ENaC egg by at least "in other embodiments, when the measurable parameter associated with the disease or condition is reduced by at least 15, 2 〇, 25, 3〇, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% consider the established clinical treatment effective 'and for; treatment of the disease or illness The therapeutically effective amount of the drug is such that the parameter is reduced by at least 15, 2, 25, 30, 35, 40, 45, 5, 55, 6, 65, 65, 7 〇, 75, 8 〇, 85, 90 or The amount of 95%. The term "pharmaceutically acceptable carrier" means a carrier for administration of a therapeutic agent. Such carriers include, but are not limited to, physiological saline, buffered saline, dextrose, m ethanol, and combinations thereof. The term specifically includes cell culture media. For pharmaceuticals administered orally, t pharmaceutically acceptable carriers include, but are not limited to, pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binders, lubricants, sweets Flavoring agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium carbonate and calcium carbonate, sodium phosphate and strontium sulphate, and lactose powder and alginic acid are suitable disintegrating agents. The binder may comprise starch and gelatin, and the lubricant, if present, will generally be stearic acid, stearic acid or talc. ^ If necessary, then (d) may be coated with a substance such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The reagents included in the pharmaceutical formulation are further described herein. Pharmaceutical compositions comprising a β-ENaC RNAi agent can be in solid form, for example, powders, granules, granules, pills, gelcaps, gelatin capsules, 154740.doc -60 · 201141489 liposomes, suppositories, chewable forms Or patch. Pharmaceutical compositions comprising beta ΕΝ & fleas may also be in liquid form such as solutions, emulsions, suspensions, elixirs or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as polyols such as glycerol or glycols including propylene glycol and polyethylene glycol, or ethanol, Cremophor EL or mixtures thereof in varying proportions in water. The composition may comprise nano-sized amorphous or crystalline particles coated with albumin or a surfactant. • Suitable carriers may include, for example, antibacterial and antifungal agents, buffers, calcium silicate, cellulose, methylcellulose, chlorobutanol, cocoa butter, colorants, dextrin, emulsifiers, enteric coatings, Flavoring agents, gelatin, isotonic agents, lecithin, magnesium stearate, flavoring agents, polyols (such as mannitol), injectable organic vinegar (such as ethyl oleate, parabens, stupid Phenol sorbic acid, polyethylene glycol, polyvinylpyrrolidine, saline buffered saline (PBS), preservatives, propylene glycol, sodium carboxymethylcellulose, sodium carbonate, sorbitol, various sugars ( These include, but are not limited to, sucrose, fructose, galactose, lactose, and trehalose), starch, tincture wax, talc, vegetable oils (such as olive oil and corn oil), vitamins, waxes, and/or humectants. The RNAi agent, preferably a carrier, comprises polydextrose and water, for example, water containing 5% dextrose (D5W). The biologically inert part of the pharmaceutical composition may be easily eroded, allowing for the timed release of the RNAi agent. The pharmaceutical composition may comprise Help with delivery, stability, efficacy Other components that reduce immunogenicity. Pharmaceutical compositions comprising a RNAi agent against P-ENaC 154740.doc -61 - 201141489 Other components of a pharmaceutical composition comprising a RNAi agent for β-ENaC may be added to aid delivery, Stability, efficacy, or reduced immunogenicity. Liposomes have previously been used for drug delivery (eg, delivery of chemotherapeutic agents). Liposomes (eg, cationic liposomes) are described in PCT Publications W002/100435A1, W003/015757A1, and WO04029213A2; Patent Nos. 5,962,016; 5,030,453; and 6,680,068; and U.S. Patent Application No. 2004/0208921. The method of making liposomes is also described in W004/002453 A1. Furthermore, neutral lipids have been incorporated into cationic liposomes. (e.g., Farhood et al., 1995). Cationic liposomes have been used to deliver RNAi agents to multiple cell types (Sioud and Sorensen 2003; U.S. Patent Application 2004/0204377; Duxbury et al., 2004; Donze and Picard, 2002). The use of neutral liposomes is disclosed in Miller et al., 1998 and U.S. Patent Application Serial No. 2003/0012812. SNALP" refers to a stable nucleic acid lipid particle. SNALP denotes a lipid microcapsule coated with a reduced aqueous phase core comprising a nucleic acid, such as a plasmon of iRNA or transcribed iRNA. SNALP is described in, for example, U.S. Patent Application Publication No. 20060240093, No. 20070135372 and International Application No. WO 2009082817.

使用基於脂質、基於胺及基於聚合物之技術的化學轉染 揭示於來自 Ambion Inc·，Austin，Tex.;及 Novagen，EMDChemical transfection using lipid-based, amine-based and polymer-based techniques is disclosed in Ambion Inc., Austin, Tex.; and Novagen, EMD

Biosciences, Inc, an Affiliate of Merck KGaA, Darmstadt, Germany) ; Ovcharenko D (2003) 「Efficient delivery of siRNAs to human primary cells.」 Ambion TechNotes 10 154740.doc -62- 201141489 (5): 15-16)之產品中。此外，s〇ng 等人（Nat Med. published online (Fete 1 0, 2003) doi: l〇.i〇38/nm828)及其他[Caplen 專人，2001 Proc· Natl. Acad. Sci. (USA)，98: 9742-9747 ; 及McCaffrey等人，Nature 414·· 34-39]揭示肝細胞可藉由將 siRNA注射至哺乳動物循環系統中有效轉染。 已使用多種分子進行細胞特異性RNAi劑傳遞。舉例而 言，魚精蛋白之核酸聚集特性已與特異性抗體合併以傳遞Biosciences, Inc, an Affiliate of Merck KGaA, Darmstadt, Germany) ; Ovcharenko D (2003) "Efficient delivery of siRNAs to human primary cells." Ambion TechNotes 10 154740.doc -62- 201141489 (5): 15-16) In the product. In addition, s〇ng et al. (Nat Med. published online (Fete 1 0, 2003) doi: l〇.i〇38/nm828) and others [Caplen, 2001 Proc· Natl. Acad. Sci. (USA), 98: 9742-9747; and McCaffrey et al., Nature 414 34-39] disclose that hepatocytes can be efficiently transfected by injection of siRNA into the mammalian circulatory system. A variety of molecules have been used for cell-specific RNAi delivery. For example, the nucleic acid aggregation properties of protamine have been combined with specific antibodies to deliver

siRNA。Song等人，2005 Nat Biotech. 23: 709-717。自組裝 聚乙二醇化聚陽離子聚伸乙基亞胺（pEI)亦已用於聚集及保 «siRNA 〇 Schiffelersf Λ, 2004 Nucl. Acids Res. 32: el49, 141-1 10 。 含有siRNA之奈米粒子接著成功傳遞至整合素過表現腫 瘤新血管中。HU-Liesk〇van等人，2〇〇5 Cancer Res 65: 8984-8992 。 本發明之RNAi劑可經例如脂質奈米粒子（LNp);中性脂 質體（NL)，聚合物奈米粒子；雙股RNA結合基元 (dsRBM)，或經⑽&amp;劑之修飾（例如共價連接於滅Μ)傳 曰貝不；；粒子（LNP)為基於自組裝陽離子脂質之系統。 此等可包含例如中性脂質（中性脂質體基質陽離子則 (對於S1RNA負载），膽固醇（用於穩定脂質體）；及pEG·月丨 質(用於穩定調配物、電荷屏蔽及延長血流中之循環卜 陽離子脂質可句冷^办,| 1 # 了匕3例如頭基、連接子、尾部及膽固醇 部。·可具有例如良好腫瘤傳遞、血液中延長之循環 154740.doc -63· 201141489 小粒子（例如小於100 nm)及腫瘤微環境穩定性（具有低pH 值且含氧量低）。 中性腊質體（NL)為基於非陽離子脂質之粒子 聚合物奈米粒子為基於自組裝聚合物之粒子。 雙股RNA結合基元（dsRBM)為將需要修飾之自組.rna 結合蛋白質。 在多個實施例中’針對j3_ENac之RNAi劑接合至一或多 個^斷化合物、報導基團、交聯劑、賦予核酸酶抗性之部 为、天然或非尋常核苷驗基、親脂性分子、膽固醇、脂 質、植物凝集素、類固醇、烏蘇醇、龍舌蘭皂苷元、薯蕷 皂苷元、萜類、三萜、菝窫皂苷元、無羈萜、表木栓醇衍 生之石膽酸、維生素、碳水化合物 '聚葡萄糖、普魯蘭、 甲破素、聚葡萄胺糖、合成碳水化合物、寡乳酸醋15 _聚 合體、天然聚合物、低分子量或中等分子量聚合物、菊 糖、環糊精、玻尿酸、蛋白質、蛋白質結合劑、靶向整合 素之分子、聚陽離子、肽、多元胺、肽模擬物及/或運鐵 蛋白。 本發明之RNAi劑可製備為包含適於投與RNAi劑之特定 方法的多種組分之醫藥組合物。 投與RNAi劑 包含β-ENaC之醫藥組合物可藉由經頰、吸入（包括吹入 及深度吸入）、經鼻、經口、非經腸、植入、經硬膜外注 射或輸注、動脈内、關節内、囊内、心内、腦室内、顱 内、皮内、肌肉内、眶内、腹膜内、脊柱内、胸骨内、鞘 154740.doc -64· 201141489 内、靜脈内、蛛膜下、囊下、皮下、表皮下、跨内皮、經 氣管、經血管、經直腸、舌下、局部及/或經***途徑投 與。此可藉由注射、輸注、皮膚貼或此項技術十已知之任 何其他方法實現。調配物可粉末化、霧化'氣溶膠化、粒 化或適當製備以供傳遞。若為液體，投與可減慢或經團式 傳遞’儘管在此項技術中已知之一些情形中，團式注射可 能導致物質經腎臟損失。 包含β-ENaC RNAi劑之醫藥組合物可使用此項技術中已 知之藥物裝置投與。舉例而言，在特定實施例中，RNAi 劑可使用無針皮下注射裝置投與，諸如美國專利第 5,399，163 號、第 5,383,851 號、第 5,312,335 號、第 5,〇64,413 號、第 4,941，880 號、第 4,790,824 號或第 4,596,556號中揭示之裝置。適用於本發明之熟知植入物及 模組的實例包括：美國專利第4,487,603號，其揭示用於在 控制速率下分配藥物之可植入微輸注泵；美國專利第 4.，486，194號’其揭示用於經皮膚投與藥物之治療裝置； 美國專利第4,447,233號，其揭示用於以精確輸注速率傳遞 藥物之藥物輸注泵；美國專利第4,447,224號，其揭示用於 連續藥物傳遞之可變流式可植入輸注設備；美國專利第 4,439，196號，其揭示具有多室隔室之滲透藥物傳遞系統； 及美國專利第4,475，196號’其揭示滲透藥物傳遞系統。熟 習此項技術者已知許多其他該等植入物、傳遞系統及模 組。 在某些實施例中’包含RNAi劑之醫藥組合物可經調配 154740.doc • 65 - 201141489 以確保適當活體内分佈。針對P_ENaC之RNAi劑之投與可 全身（整體）或尤其靶向表現P_ENaC(或過表現p_ENaC或顯 示β-ENaC高活性）之組織或器官，諸如肺、腎臟、結腸及 腺。靶向此等特定組織或器官之方法揭示於本文中及/或 為此項技術中所已知。舉例而言’其可調配為脂質體。製 造脂質體之方法參看例如美國專利4,522,8n ; 5,374,548及 5,399,331。脂質體可包含選擇性傳入特異性細胞或器官中 的一或多個部分，因此提高靶向藥物傳遞（參看例如vv Ranade (1989) J. Clin. Pharmacol. 29: 685) 〇 實例乾向部分包括葉酸鹽或生物素（參看例如L〇w等人之 美國專利5,416,016);甘露糖（Umezawa等人，（1988) Biochem. Biophys. Res. Commun. 153: 1038);抗體（P.G. Bloeman 等人，（1995) FEBS Lett. 357: 140 ; M. Owais 等人， (1995) Antimicrob. Agents Chemother. 39: 180);界面活性 劑蛋白質 A受體（Briscoe等人，（1995) Am. J. Physiol. 1233: 134)，可包含本發明調配物以及所發明分子之組分的不同 物質；pl20(Schreier等人，（1994) J. Biol· Chem. 269: 9090);亦參看 K. Keinanen; M.L. Laukkanen (1994) FEBS Lett. 346: 123 ； J.J. Killion; I.J. Fidler (1994)siRNA. Song et al., 2005 Nat Biotech. 23: 709-717. Self-assembly PEGylated polycationic polyethylenimine (pEI) has also been used for aggregation and conservation «siRNA 〇 Schiffelersf Λ, 2004 Nucl. Acids Res. 32: el49, 141-1 10 . Nanoparticles containing siRNA are then successfully delivered to integrin-overexpressing tumor neovasculature. HU-Liesk〇van et al., 2〇〇5 Cancer Res 65: 8984-8992. The RNAi agent of the present invention may be modified, for example, by a lipid nanoparticle (LNp); a neutral liposome (NL), a polymer nanoparticle; a double-stranded RNA binding motif (dsRBM), or a (10) &amp; The valence is linked to the cockroach), and the granules (LNP) are systems based on self-assembled cationic lipids. Such may include, for example, neutral lipids (neutral liposome matrix cations (for S1 RNA loading), cholesterol (for stabilizing liposomes); and pEG·moon enamel (for stable formulation, charge shielding, and prolonged blood flow) In the circulation of cationic lipids can be cold, ^ 1 # 匕 3 such as head base, linker, tail and cholesterol. · Can have, for example, good tumor transmission, prolonged circulation of blood 154740.doc -63· 201141489 Small particles (eg less than 100 nm) and tumor microenvironmental stability (low pH and low oxygen content) Neutral waxy bodies (NL) are non-cationic lipid-based particle polymer nanoparticles based on self-assembly Particles of the polymer. The double-stranded RNA binding motif (dsRBM) is a self-assembled .rna binding protein that will require modification. In various embodiments, the RNAi agent for j3_ENac is conjugated to one or more compounds, reporters Group, cross-linking agent, nuclease-resistant part, natural or unusual nucleoside test, lipophilic molecule, cholesterol, lipid, plant lectin, steroid, ursolic, agave saponin, diosgenin yuan Terpenoids, triterpenoids, saponins, sorghum, sulphate-derived lithocholic acid, vitamins, carbohydrates, polydextrose, pullulan, methionin, polyglucosamine, synthetic carbohydrates, Oligolactic vinegar 15 _polymer, natural polymer, low molecular or medium molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein binder, molecules targeting integrins, polycations, peptides, polyamines, Peptide mimetics and/or transferrin. The RNAi agent of the present invention can be prepared as a pharmaceutical composition comprising a plurality of components suitable for the particular method of administering a RNAi agent. Administration of a pharmaceutical composition comprising a βi-ENaC can be administered to an RNAi agent. By buccal, inhalation (including insufflation and deep inhalation), nasal, oral, parenteral, implantation, epidural injection or infusion, intra-arterial, intra-articular, intra-capsular, intracardiac, intraventricular , intracranial, intradermal, intramuscular, intraorbital, intraperitoneal, intraspinal, sternal, sheath 154740.doc -64· 201141489, intravenous, subarachnoid, subcapsular, subcutaneous, subepidermal, transendothelial, Transtracheal, transvascular, transrectal , sublingual, topical and/or vaginal route administration. This can be achieved by injection, infusion, skin patch or any other method known in the art. The formulation can be powdered, atomized, aerosolized, granulated. Or suitable for delivery. If liquid, administration can be slowed or conjugated. 'Although in some cases known in the art, bolus injections may result in loss of material through the kidney. Contains β-ENaC RNAi The pharmaceutical composition of the agent can be administered using a pharmaceutical device known in the art. For example, in certain embodiments, the RNAi agent can be administered using a needleless hypodermic injection device, such as U.S. Patent No. 5,399,163, Apparatus disclosed in U.S. Patent Nos. 5,383,851, 5, 312, 335, 5, pp. 64, 413, 4,941, 880, 4, 790, 824, or 4, 596, 556. Examples of well-known implants and modules suitable for use in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,486,194 ' </ RTI> discloses a therapeutic device for transdermal administration of a drug; U.S. Patent No. 4,447,233, the disclosure of which is incorporated herein incorporated by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire disclosure A flow-through implantable infusion device; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having a multi-chamber compartment; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems and modules are known to those skilled in the art. In certain embodiments, a pharmaceutical composition comprising an RNAi agent can be formulated 154740.doc • 65 - 201141489 to ensure proper in vivo distribution. The administration of the RNAi agent against P_ENaC may be systemic (overall) or specifically targeted to tissues or organs exhibiting P_ENaC (or overexpressing p_ENaC or showing high activity of β-ENaC), such as the lungs, kidneys, colon and glands. Methods of targeting such specific tissues or organs are disclosed herein and/or are known in the art. For example, it can be formulated as a liposome. For a method of making liposomes, see, for example, U.S. Patent Nos. 4,522,8n; 5,374,548 and 5,399,331. Liposomes can comprise selective introduction into one or more parts of a specific cell or organ, thereby enhancing targeted drug delivery (see, eg, vv Ranade (1989) J. Clin. Pharmacol. 29: 685). Including folate or biotin (see, e.g., U.S. Patent 5,416,016 to L.w et al.); mannose (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153: 1038); antibody (PG Bloeman et al.) (1995) FEBS Lett. 357:140; M. Owais et al., (1995) Antimicrob. Agents Chemother. 39: 180); Surfactant Protein A Receptor (Briscoe et al., (1995) Am. J. Physiol 1233: 134), a different substance which may comprise a formulation of the invention and a component of the molecule of the invention; pl20 (Schreier et al., (1994) J. Biol. Chem. 269: 9090); see also K. Keinanen; ML Laukkanen (1994) FEBS Lett. 346: 123 ; JJ Killion; IJ Fidler (1994)

Immunomethods 4: 273) ° 本發明因此涵蓋用於治療β-ENaC相關疾病的包含一或 多種針對β-ENaC之RNAi劑的醫藥組合物，其可視情況包 含多種修飾及/或其他組分。 β-ENaC相關疾病 154740.doc •66· 201141489 本發明涵蓋針對β-ENaC之RNAi劑，及向人類及非人類 動物投與RNAi劑以治療各種p_ENaC相關疾病。 「β-ENaC相關疾病」意謂與j3_ENaC之含量、表現及/或 活性的功能障礙有關之任何疾病’及/或可藉由調節卜 ENaC之含量、表現及/或活性治療及/或改善的任何疾病。 詳言之’其包括囊腫性纖維化、1型假醛固酮過少症 (PHA1 )、李德爾症候群、高血壓、驗中毒、低奸血症及肥 胖相關之南血壓。 「囊腫性纖維化」或「CF」意謂與囊腫性纖維化跨膜傳 導調節（CFTR)基因之突變有關的常見遺傳性疾病。cFtr 編碼cAMP依賴性C1-通道且調節ENaC。在CF氣管上皮 中’ CFTR介導之C1-分泌有缺陷及ENaC介導之Na+吸收增 加。CF氣管·中之此等離子傳輸缺陷使氣管表面液體（asl) 容量耗竭、黏液清除有缺陷及黏液黏附，表明ASL容量耗 竭為CF肺病之發病機制的關鍵機制。在實驗小鼠中， ENaC之氣管特異性過表現證明加速之單獨Na+傳輸足以產 生ASL容量耗竭及CF樣肺病，包括氣管黏液阻塞、杯狀細 胞化生、慢性嗜中性氣管發炎、細菌病原體清除異常及最 終死亡。參看Zhou等人，2008及其中引用之參考文獻。 「李德爾症候群」意謂高血壓之常染色體顯性遺傳形 式，特徵為早期且嚴重高血壓，通常伴隨代謝鹼中毒及低 鉀血症’特徵為醛固酮過量之所有病徵（康氏症候群 (Conn’s syndrome))。 然而’酸固_之血漿含量較低。因此，李德爾症候群亦 154740.doc •67· 201141489 稱為假多駿固_症。高血壓之此嚴重形式對使用低鹽飲食 及Na通道抑制劑（留K+利尿劑）治療起反應，表明ENaC之 主要缺陷調節。該疾病與γ-ENaC突變、及亦β-ENaC之若 干突變（「PY」基元中之P615S、P616L及Y618H，其具有 ΡΡΧΥ之共同序列；及亦 R564st、W574st ' 579del32、 Q589st ' T592fr、A593fr及 R595fr，其中「fr」為讀框轉 移’「del」為缺失，且「st」為提前終止密碼子）有關。 此等突變引起相較於野生型ENaC高活性之Na+通道過表 現。突變亦防止通道下調，通常出現胞内Na+升高；儘管 馬胞内Na+濃度’但具有李德爾突變之ENaC通道仍為高度 活性狀態。因此’李德爾症候群之突變ENaC之含量及/或 活性可由針對β-ENaC之siRNA調節，或該siRNA與李德爾 症候群之已知治療（諸如低鹽飲食及Na+通道抑制劑（留κ+ 利尿劑））組合。 β-ENaC相關疾病之其他資訊參看例如Hummier等人， 1999. Am. J. Physiol. Gastrointest. Liver Physiol. 276: 567-571 〇 「肥胖相關之高血壓」意謂與肥胖有關或相關之高血 壓，及其類似疾病。肥胖與高血壓相關。已提出多種機制 來解釋此相互關係，包括（在肥胖中）增加之交感神經活 性；增加之腎素-血管收縮素-醛固酮系統活性；增加之心 輸出量；及器官周圍間隙脂肪產生的增加之機械壓力；高 姨島素血症及/或胰島素抗性。腎臟之鈉滯留可由任一此 等機制引起。在連接管及集合管中，經ENaC出現鈉再吸 154740.doc 201141489 收。Zucker大鼠（肥胖之模型動物）腎臟中p_ENaC之含量增 加。Immunomethods 4: 273) ° The present invention thus encompasses pharmaceutical compositions comprising one or more RNAi agents against β-ENaC for use in the treatment of β-ENaC-associated diseases, optionally containing various modifications and/or other components. β-ENaC-associated diseases 154740.doc • 66· 201141489 The present invention encompasses RNAi agents against β-ENaC, and administration of RNAi agents to humans and non-human animals to treat various p_ENaC-related diseases. "β-ENaC-related disease" means any disease associated with dysfunction of the content, performance and/or activity of j3_ENaC' and/or may be treated and/or improved by modulating the content, performance and/or activity of ENaC Any disease. In detail, it includes cystic fibrosis, type 1 pseudoaldosteronism (PHA1), lider syndrome, hypertension, poisoning, low vaginal blood, and obesity-related southern blood pressure. "Cellular fibrosis" or "CF" means a common hereditary disease associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. cFtr encodes a cAMP-dependent C1-channel and regulates ENaC. In the CF tracheal epithelium, 'CFTR-mediated C1-secretion is defective and ENaC-mediated Na+ uptake is increased. This plasma transport defect in the CF trachea depletes the volume of the tracheal surface fluid (asl), defects in mucus clearance, and mucus adhesion, indicating that ASL volume depletion is a key mechanism for the pathogenesis of CF lung disease. In experimental mice, the tracheal-specific overexpression of ENaC demonstrated accelerated local Na+ transport sufficient to produce ASL volume depletion and CF-like lung disease, including tracheal mucus obstruction, goblet cell metaplasia, chronic neutrophilic tracheal inflammation, bacterial pathogen clearance Abnormal and ultimately dead. See Zhou et al., 2008 and references cited therein. "Ledel syndrome" means an autosomal dominant form of hypertension characterized by early and severe hypertension, usually accompanied by metabolic alkalosis and hypokalemia, characterized by all signs of aldosterone excess (Conn's syndrome) )). However, the plasma content of 'acid-solids' is low. Therefore, the Lidell syndrome is also 154740.doc •67· 201141489 is called the fake multi-juno _ disease. This severe form of hypertension responds to treatment with a low-salt diet and a Na-channel inhibitor (K+ diuretic), indicating a major defect in ENaC regulation. The disease is associated with a γ-ENaC mutation, and also a mutation of β-ENaC (P615S, P616L and Y618H in the "PY" motif, which has a common sequence of ΡΡΧΥ; and also R564st, W574st '579del32, Q589st 'T592fr, A593fr And R595fr, where "fr" is the reading frame transfer '"del" is missing, and "st" is the early termination codon). These mutations resulted in an overexpression of Na+ channels that were highly active compared to wild-type ENaC. Mutations also prevent down-regulation of the channel, usually with an increase in intracellular Na+; although the Na+ concentration in horse cells, the ENaC channel with Liddell mutation is still highly active. Therefore, the content and/or activity of the 'Leder syndrome mutation ENaC can be regulated by siRNA against β-ENaC, or the known treatment of the siRNA and lider syndrome (such as low-salt diet and Na+ channel inhibitor (left κ+ diuretic) ))combination. For additional information on β-ENaC-related diseases see, for example, Hummier et al., 1999. Am. J. Physiol. Gastrointest. Liver Physiol. 276: 567-571 肥胖 "obesity-related hypertension" means hypertension associated with or associated with obesity , and similar diseases. Obesity is associated with high blood pressure. Various mechanisms have been proposed to explain this interrelationship, including increased sympathetic activity (in obesity); increased renin-angiotensin-aldosterone system activity; increased cardiac output; and increased fat production around the interstitial space Mechanical stress; sorghum and/or insulin resistance. Sodium retention in the kidney can be caused by any of these mechanisms. In the connecting tube and the collecting tube, sodium is resorbed by ENaC 154740.doc 201141489. The content of p_ENaC in the kidneys of Zucker rats (model animals of obesity) increased.

Bickel 等人，2001 Am. J. Physiol· Renai phySi〇i. 281: 639-648。此及其他鈉轉運體之豐度相對增加，而其他納 轉運體未降低’可能導致管鈉再吸收增加。因此，腎臟納 轉運體豐度之此等改變可能在肥胖哺乳動物（包括人類）中 產生及/或維持ifj血壓中起'定作用。 # 「1型假酸固酮過少症」、「ΡΗΑ1」、「ΡΗΑ-1」及其類似 術語意謂特徵為鹽皮質激素終器抗性之異源性臨床症候 群，亦即儘管醛固酮含量升高，但尿液損失Na+且κ+*** 降低。此症狀之嚴重形式以常染色體隱性性狀遺傳，有時 導致低鈉血症、低血壓及高鉀血症之致死事件，且顯示若 干器官（腎臟、唾液腺、汗腺及結腸）中Na+傳輸之改變。 在顯不此形式PHA-1之若干家族中，發現三種ENaC子單元 之任一者中與突變之關聯（包括β-ENaC中之G37S)。 •常染色體顯性遺傳模式之較不嚴重形式之PHA-1多數為 幼年期間有症狀且隨年齡改善。參看Huinmier等人，1999.Bickel et al., 2001 Am. J. Physiol· Renai phySi〇i. 281: 639-648. The abundance of this and other sodium transporters is relatively increased, while other nanocarriers are not reduced' may result in increased sodium reabsorption. Thus, such changes in renal nanocarrier abundance may play a role in the production and/or maintenance of ifj blood pressure in obese mammals, including humans. # "Type 1 pseudo-acid ketosis", "ΡΗΑ1", "ΡΗΑ-1" and similar terms means a heterogeneous clinical syndrome characterized by resistance to mineralocorticoid receptors, that is, despite elevated aldosterone levels However, urine loss Na+ and κ+ excretion decreased. The severe form of this symptom is inherited by autosomal recessive traits, sometimes leading to hyponatremia, hypotension, and hyperkalemia, and shows changes in Na+ transmission in several organs (kidney, salivary gland, sweat gland, and colon). . In several families of this form of PHA-1, the association with mutations (including G37S in β-ENaC) was found in any of the three ENaC subunits. • The less severe forms of the autosomal dominant pattern of PHA-1 are mostly symptomatic and improve with age during childhood. See Huinmier et al., 1999.

Am. J. Physiol. Gastrointest. Liver Physiol. 276: 567-571。 針對β-ENaC之RNAi劑可用於治療β-ENaC相關疾病，尤 其與β-ENaC之表現、活性及/或含量改變有關的彼等疾 病。 RNAi劑用於治療p_ENaC相關疾病之用途 本文所述之針對β-ENaC之RNAi劑可調配成可向人類或 非人類動物投與的醫藥組合物。此等組合物可包含一或多 154740.doc -69- 201141489 種RNAi劑，及視情況選用之適用於治療β·ΕΝ^相關疾病 的其他治療。其可作為早期/預防性治療的一部分投與， 且可以/。療有效劑量投與。醫藥組合物可包含醫藥載劑且 可藉由此項技術中已知之任何方法投與。本發明之此等多 種態樣在下文中另外詳細描述。 針對β-ENaC之RNAi劑可向人類及非人類動物投與以治 療β-ENaC相關疾病。 在本發明之一實施例中，可向非人類動物投與包含卜 ENaC RNAi劑之組合物。舉例而言，組合物可給予雞、火 雞、家畜動物(諸如綿羊、#、馬、牛等）、伴侣動物(例如 貓及犬），且可具有治療囊腫性纖維化、丨型假醛固酮過少 症（PHA1)、李德爾症候群、高血壓、鹼中毒、低鉀血症及 肥胖相關之高血壓及類似疾病之功效。在各情形中針對 β-ENaC之RNAi劑將經選擇以匹配動物之基因組之β_ΕΝ&amp;(： 的序列’且特定言之含有與彼動物基因組之所有其他基因 的至少1 nt錯配。本發明之RNAi劑因此可用於治療人類及 非人類動物之β-ENaC相關疾病。 如本文在β-ENaC表現中所用，術語「治療」及其類似 術語係指緩解或改善β-ENaC表現所介導之病理學過程。在 本揭示關於下文引用之任何其他病狀（除β-ENaC表現所介 導之病理學過程之外）範圍内，術語「治療」及其類似術 語意謂減輕或緩解至少一種與該病狀有關的症狀，或減緩 或逆轉該病狀之進展或預期進展，諸如減緩脂質病症（諸 如動脈粥樣硬化）之進展。 154740.doc -70· 201141489 治療」亦意謂患者病況之防治、治療、治癒或顯示改 良或不存在身體狀況退化之任何其他改變β Γ治療」意謂 治療β-ENaC相關疾病（例如囊腫性纖維化、1型假路固酮過 少症（PHA1)、李德爾症候群、高血壓、鹼中毒、低鉀血症 及肥胖相關之高血壓），或任何適當治療患者患有之任何 其他疾病。如本文所用’術語「治療」係指防治性及預防 性治療及治癒或疾病改善治療，包括治療處於感染疾病風 險或疑似患病之患者’以及已生病或診斷為罹患病況之患 者。術語「治療」亦指維持及/或促進未罹患疾病但可能 易於產生不健康狀況（諸如氮失衡或肌肉損失）之個體的健 康。在一個實施例中，「治療」不涵蓋預防疾病狀態。因 此，本發明適用於受|3_ENaC相關疾病折磨之個體或易患β_ ENaC相關疾病之個體中抑制p_ENaC基因表現及/或治療p_ ENaC相關疾病《受β-ENaC相關疾病「折磨」之個體已顯 現疾病之可偵測症狀特徵，或另外已顯示臨床上曾暴露於 或攜帶β-ENaC相關疾病病原體或標誌。作為非限制性實 例’受β-ENaC相關疾病折磨之個體可能顯示外表症狀 (outward symptom);或可能不顯示外表症狀，但經臨床測 試可能顯示攜帶與|3_ENaC相關疾病有關之蛋白質標誌，或 與血液中之病原體有關之蛋白質或遺傳物質。 若較早而非較晚投與，則一些P_ENaC相關疾病的早期 治療可能更有效。預防性早期投與阿米洛利（ENaC抑制劑） 適於治療CF模型小鼠，而較晚投與則不能。類似地，在 CF中以抗微生物劑早期干預比感染後治療更有效。Zh〇u 154740.doc •71 · 201141489 等人，2008。因此，在-特定實施例中，針對卜Η·之 RNAi劑係早期投與、在疾病表現之前投與及/或作為預防 劑投與，而非在疾病確立後投與。 β-ENaC相關疾病之治療可包含多種治療，包含ρ RNAi劑，且視情況另外包含可為方法（或程序）或額外組合 物（例如試劑或額外RNAi劑）的額外治療。 RNAi劑之劑量及有效量 本發明之RNAi劑以對有需要患者 投與。 之治療有效量的劑量Am. J. Physiol. Gastrointest. Liver Physiol. 276: 567-571. RNAi agents against β-ENaC are useful in the treatment of β-ENaC-related diseases, particularly those associated with changes in the performance, activity and/or content of β-ENaC. Use of RNAi Agents for the Treatment of p_ENaC Related Diseases The RNAi agents described herein for β-ENaC can be formulated into pharmaceutical compositions that can be administered to human or non-human animals. Such compositions may comprise one or more of 154740.doc-69-201141489 RNAi agents, and optionally other treatments suitable for the treatment of β-ΕΝ^ related diseases. It can be administered as part of an early/preventive treatment and can be /. The therapeutically effective dose is administered. The pharmaceutical compositions can comprise a pharmaceutical carrier and can be administered by any method known in the art. These various aspects of the invention are described in additional detail below. RNAi agents against β-ENaC can be administered to humans and non-human animals to treat β-ENaC-related diseases. In one embodiment of the invention, a composition comprising an ENaC RNAi agent can be administered to a non-human animal. For example, the composition can be administered to chickens, turkeys, livestock animals (such as sheep, #, horses, cattle, etc.), companion animals (such as cats and dogs), and can have treatment for cystic fibrosis, sputum-type pseudoaldosterone too little Efficacy (PHA1), Liddell syndrome, hypertension, alkalosis, hypokalemia, and the effects of obesity-related hypertension and similar diseases. The RNAi agent for β-ENaC in each case will be selected to match the β_ΕΝ&amp;(: sequence of the animal's genome and, in particular, contains at least 1 nt mismatch with all other genes of the animal's genome. RNAi agents are therefore useful in the treatment of β-ENaC-associated diseases in humans and non-human animals. As used herein in the expression of β-ENaC, the term "treatment" and similar terms refer to the pathology mediated by the amelioration or improvement of β-ENaC expression. In the context of the present disclosure regarding any other condition cited below (other than the pathological process mediated by the expression of β-ENaC), the term "treatment" and the like means to mitigate or alleviate at least one Symptoms associated with the condition, or slowing or reversing the progression or expected progression of the condition, such as slowing the progression of a lipid disorder such as atherosclerosis. 154740.doc -70· 201141489 Treatment also means prevention and treatment of the patient's condition, Treatment, cure, or any other change that shows improvement or absence of deterioration of the body condition β Γ treatment means “treatment of β-ENaC-related diseases (eg cystic fibrosis, type 1) Lung ketosis (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and obesity-related hypertension, or any other disease that is appropriate for the treatment of a patient. As used herein, the term 'treatment' Means a preventive and preventive treatment and a cure or improvement in the treatment of a disease, including the treatment of a patient at risk of or at risk of illness or a patient who has become ill or diagnosed as having a condition. The term "treatment" also refers to maintenance and/or Promoting the health of an individual who is not suffering from a disease but may be prone to unhealthy conditions, such as nitrogen imbalance or muscle loss. In one embodiment, "treatment" does not encompass the prevention of disease states. Therefore, the present invention is applicable to diseases associated with |3_ENaC-related diseases. Inhibition of p_ENaC gene expression and/or treatment of p_ENaC-related diseases in individuals who are susceptible to β_ENaC-related diseases. Individuals who have been afflicted with β-ENaC-related diseases have developed detectable symptom characteristics of the disease, or have been shown otherwise Clinically exposed or carried with β-ENaC-related disease pathogens or markers. As a non-limiting example, 'accepted by β-ENaC phase Individuals who are afflicted with the disease may show outward symptoms; or may not show signs of appearance, but clinical tests may indicate that they carry protein markers associated with diseases associated with |3_ENaC, or proteins or genetic material associated with pathogens in the blood. Early treatment of some P_ENaC-related diseases may be more effective if administered earlier rather than later. Prophylactic early administration of amiloride (ENaC inhibitor) is suitable for treatment of CF model mice, and later cast No. Similarly, early intervention with antimicrobial agents in CF is more effective than post-infection treatment. Zh〇u 154740.doc •71 · 201141489 et al., 2008. Thus, in a particular embodiment, the RNAi agent for diarrhea is administered early, administered prior to disease manifestation, and/or administered as a prophylactic agent, rather than administered after the disease is established. Treatment of a β-ENaC-related disease can comprise a variety of therapies, including a ρ RNAi agent, and optionally additional treatments that can be methods (or procedures) or additional compositions (e.g., agents or additional RNAi agents). Dosage and Effective Amount of RNAi Agent The RNAi agent of the present invention is administered to a patient in need thereof. Therapeutically effective amount of the dose

「有效量」或「治療有效量」為治療個體之疾病或醫尋 病況的量，或更一般而言，向個體提供營養、生理學或譽 學益處之量。如本文所用，「治療有效量」及「防二: 量」-詞係指在P-ENaC表現介導之病理學過程或卜· 表現介導之病理學過程的外顯症狀的治療、預防或管理令 提供治療益處之量。治療纽之料量可由—般醫學從澤 人員谷易地測定，且可視此項技術中已知之因素變化，舞 如β-ENaC表現介導之病理學過程之類型 齡—表現介導之病理學過程的階段及抑二= 表現；丨導之病理學過程的其他試劑之投盥。 月在trrr實施例中，患者為至’少約…、㈣ 2〇、3〇、4〇、50、55、60、65、7 歲。在多個實施例中，患者不超過約卜3、6或9個或 卜5、10、20、30、40、50、55、60…，'^。、 90或1〇〇歲。在多個實施例中，患者體重為至少約$、1〇、 154740.doc -72· 201141489 15、20、30、40、50、60、70 ' 80 ' 90 ' 100、120、 140 、 160 、 180 ' 200 、 220 、 240 、 260 ' 280 、 300 、 320 、 340、360、3 80或400磅（lbs)。在多個實施例中，患者體重 不超過約 5、10、15、20、30、40、50、60、70、80 ' 90 ' 100 ' 120、140 ' 160 ' 180 ' 200、220、240 ' 260 ' 280、300、320、340、360、380或400 lbs。An "effective amount" or "therapeutically effective amount" is an amount that treats an individual's disease or seeks a condition, or more generally, provides an individual with a nutritional, physiological or academic benefit. As used herein, "therapeutically effective amount" and "anti-two: amount" - words refer to the treatment, prevention or treatment of the external symptoms of a pathological process mediated by P-ENaC expression or a pathological process mediated by performance. The management order provides the amount of therapeutic benefit. The amount of therapeutic material can be determined by the general medicine from Zeren Valley, and can be changed according to factors known in the art, such as the type-age-expressed pathology of the pathological process mediated by β-ENaC expression. The stage of the process and the second = performance; the investigation of other reagents in the pathological process of the sputum. In the trrr embodiment, the patients were ~ less than ..., (4) 2, 3, 4, 50, 55, 60, 65, 7 years old. In various embodiments, the patient does not exceed about 3, 6, or 9 or 5, 10, 20, 30, 40, 50, 55, 60..., '^. , 90 or 1 year old. In various embodiments, the patient weighs at least about $, 1〇, 154740.doc -72·201141489 15, 20, 30, 40, 50, 60, 70 '80 '90 '100, 120, 140, 160, 180 ' 200 , 220 , 240 , 260 ' 280 , 300 , 320 , 340 , 360 , 3 80 or 400 lbs (lbs). In various embodiments, the patient weighs no more than about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80 '90 '100 '120, 140 '160 '180 '200, 220, 240 ' 260 '280, 300, 320, 340, 360, 380 or 400 lbs.

在本發明之多個實施例中，劑量[僅量測活性成分]可為 至少約 1、5、10、25、50、100、200、250、300、250、 400 、 450 、 500 、 550 、 600 、 650 、 700 ' 750 、 800 、 850 、 900、950 或 1000 ng，1、5、10、25、50、100、200、 250 、 300 、 250 ' 400 ' 450 ' 500 、 550 、 600 、 650 、 700 ' 750、800、850、900、950 或 1000 pg，1、5、10、25、 50、100、200、250、300、250、400、450、500、550、 600 、 650 、 700 、 750 、 800 、 850 、 900 、 950或1000 mg 。 在多個實施例中，劑量可不超過約10、25、50、100、 200、250、300、250、400、450、500、550、600、650、 700、750、800、850、900、950 或 1000 mg。在多個實施 例中，劑量可至少每天投與一次以上、每天一次、每週一 次以上、每週一次、每兩週一次、每月一次及/或每2、 3、4、5、6、7、8、9、10、11 或 12 個月一次、或其組 合。 在多個實施例中，劑量與個體之體重或體表面積有關。 實際劑量可變化以使獲得的活性成分之量對特定患者、組 合物及投與模式有效，而對患者無毒。所選劑量將視多種 154740.doc -73- 201141489 藥物動力學因素而定，包括所採用特定RNAi劑之活性、 投與途徑、RNAi劑排出速率、治療持續時間、與RNAi劑 組合使用之其他藥物、化合物及/或物質、患者之年齡、 隱別、體重、病況、—般健康狀況及先前病史及醫藥技術 中熟知的類似因素。具有—般技術之醫師或獸醫可容易地 測定所需RNAi劑之有效量。適合劑量將為有效產生治療 作用之最低劑量，或足夠低以產生治療作用而不引起副作 用的劑量。 除了治療有效劑量之一或多種針對p_ENaCi RNAi劑之 外，本發明之醫藥組合物可包含額外疾病治療或與其他疾 病治療結合使用，其與RNAi劑協同起作用。舉例而言， 醫藥組合物可包含針對ENaC之額外拮抗劑，諸如留鉀利 尿劑、阿米洛利及胺苯喋啶。額外治療可與醫藥組合物一 起投與’包括（非限制性實例）飲食鹽攝取調節。當用於治 療囊腫性纖維化時，醫藥組合物可與此項技術中已知之多 種藥物及療法結合使用，包括（但不限於）抗生素、DNase 療法、沙丁胺醇、N-乙醯半胱胺酸、呼吸療法、叩診療 法、有氧運動及治療與囊腫性纖維化有關之疾病（例如腹 瀉、骨質疏鬆症、糖尿病、出血等）的多種藥物及療法。 針對p-ENaC之RNAi劑的額外實施例 在特定實施例中’本發明涵蓋包含一或多種p_ENaC RNAi劑之組合物《在一實施例中，本發明包含具有有義 股及反義股之RNAi劑。在一實施例中，反義股由、基本 上由具有例如表1中所列之RNAi劑的反義股的序列組成或 154740.doc •74· 201141489 包含具有例如表1中所列之RNAi劑的反義股的序列。在一 實施例中’反義股由、基本上由與例如表1中所列之任何 RNAi劑的反義股有〇、1、2或3個錯配的序列組成或包含 與例如表1中所列之任何RNAi劑的反義股有〇、1、2或3個 錯配的序列。在一實施例中，反義股由例如表1中所列之 RNAi劑之反義股序列組成’且另外包含〇、1、2、3、4、 5、6、7、8、9或10個核苷酸。在一實施例中，反義股由 與例如表1中所列之RNAi劑之反義股有〇、1、2或3個錯配 的序列組成，且另外包含0、1、2、3、4、5、6、7、8、9 或10個核苷酸。 在另一實施例中’本發明之組合物不包含例如表1中所 列之任何特定個別RNAi劑。在本發明之另一實施例中， 針對β-ENaC之RNAi劑不包含專利或科學文獻中揭示之任 何β-ENaC RNAi劑的序列，例如美國專利申請案第 60/346,069 號（PCT/US02/41850)及 Hyde 等人，2009，The 23rd North American Cystic Fibrosis Conference,In various embodiments of the invention, the dose [measured only active ingredient] may be at least about 1, 5, 10, 25, 50, 100, 200, 250, 300, 250, 400, 450, 500, 550, 600, 650, 700 '750, 800, 850, 900, 950 or 1000 ng, 1, 5, 10, 25, 50, 100, 200, 250, 300, 250 '400 '450 '500, 550, 600, 650 , 700 '750, 800, 850, 900, 950 or 1000 pg, 1, 5, 10, 25, 50, 100, 200, 250, 300, 250, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg. In various embodiments, the dosage may not exceed about 10, 25, 50, 100, 200, 250, 300, 250, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950. Or 1000 mg. In various embodiments, the dose can be administered at least once a day, once a day, once a week, once a week, once every two weeks, once a month, and/or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or a combination thereof. In various embodiments, the dose is related to the individual's body weight or body surface area. The actual dosage can be varied so that the amount of active ingredient obtained is effective for a particular patient, composition, and mode of administration, and is non-toxic to the patient. The selected dose will depend on a number of 154740.doc -73- 201141489 pharmacokinetic factors, including the activity of the particular RNAi agent employed, the route of administration, the rate of RNAi agent expulsion, duration of treatment, and other drugs used in combination with the RNAi agent. , Compounds and/or Substances, Age, Hidden, Weight, Condition, General Health Status, and Prior Medical History and Similar Factors Well Known in Medical Technology. A physician or veterinarian of ordinary skill can readily determine the effective amount of the desired RNAi agent. A suitable dose will be the lowest dose effective to produce a therapeutic effect, or a dose that is low enough to produce a therapeutic effect without causing side effects. In addition to one or more therapeutically effective doses for the p_ENaCi RNAi agent, the pharmaceutical compositions of the present invention may comprise additional disease treatment or in combination with other disease treatments which act synergistically with the RNAi agent. For example, the pharmaceutical composition may comprise additional antagonists to ENaC, such as a potassium-sparing diuretic, amiloride, and amphetamine. Additional treatment can be administered with a pharmaceutical composition&apos; including, by way of non-limiting example, dietary salt uptake regulation. When used to treat cystic fibrosis, pharmaceutical compositions can be used in combination with a variety of drugs and therapies known in the art including, but not limited to, antibiotics, DNase therapy, salbutamol, N-acetylcysteine, Respiratory therapy, percussion therapy, aerobic exercise, and a variety of medications and therapies for diseases associated with cystic fibrosis (eg, diarrhea, osteoporosis, diabetes, bleeding, etc.). Additional Examples of RNAi Agents for p-ENaC In a particular embodiment, the invention encompasses compositions comprising one or more p_ENaC RNAi agents. In one embodiment, the invention comprises RNAi having sense and antisense strands Agent. In one embodiment, the antisense strand consists, consists essentially of a sequence having an antisense strand, such as the RNAi agent listed in Table 1, or 154740.doc • 74· 201141489 comprises, for example, the RNAi agents listed in Table 1. The sequence of antisense stocks. In one embodiment, the antisense strand consists, consists essentially of, or comprises, for example, a sequence having a mismatch, 1, 2 or 3 mismatches with an antisense strand of any of the RNAi agents listed in Table 1. The antisense strand of any of the listed RNAi agents has a sequence of 〇, 1, 2 or 3 mismatches. In one embodiment, the antisense strand consists of, for example, an antisense strand sequence of the RNAi agent listed in Table 1 and additionally comprises 〇, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 Nucleotides. In one embodiment, the antisense strand consists of a sequence of 〇, 1, 2 or 3 mismatches with an antisense strand such as the RNAi agent listed in Table 1, and additionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides. In another embodiment, the compositions of the present invention do not comprise any of the specific individual RNAi agents listed, for example, in Table 1. In another embodiment of the invention, the RNAi agent for β-ENaC does not comprise a sequence of any of the β-ENaC RNAi agents disclosed in the patent or scientific literature, for example, U.S. Patent Application Serial No. 60/346,069 (PCT/US02/ 41850) and Hyde et al., 2009, The 23rd North American Cystic Fibrosis Conference,

Minneapolis，2009 年 10 月 14-17 日；或可作為 sc-42418(及相 關產物）自 Santa Cruz Biotechnology，Santa Cruz，CA獲得 者。 針對β-ENaC之RNAi劑的特定實施例 本文揭示針對β-ENaC之RNAi劑的多個具體實施例。實 例雙鏈體序列提供於本文及例如表1令。本發明之特定實 施例包括包含與例如表1中列出之RNAi劑的彼等有〇、1、 2或3個nt或bp不同（例如〇、1、2或3個錯配）之序列的RNAi 154740.doc -75- 201141489 劑。 錯配在本文中定義為當兩個序列最大程度比對及比較時 驗基序列或長度之間的差異。錯配定義為一個序列的鹼基 與另一序列之鹼基不匹配的位置。因此，舉例而言，若一 序列之位置具有特定驗基（例如A)，且另一序列之相應位 置具有不同鹼基（例如G)，則計數錯配。 例如’若一個序列之位置具有鹼基（例如A)，且另一序 列之相應位置不具有驗基（例如彼位置為包含峨酸酯-糖骨 架但無驗基之無驗基核苷酸），則亦計數錯配。任一序列 (或有義股或反義股）中之單股切口不計為錯配。因此，作 為非限制性實例’若一序列包含序列AG，但另一序列包 含序列AG且在A與G之間具有單股切口，則不計數錯配。 驗基修飾亦不視為錯配。因此，若一序列包含c，且另一 序列在同一位置包含經修飾c(例如2，_修飾），則將不計數 錯配。 在一特定實施例中’本發明包含具有反義股之RNAi 劑’該反義股包含有0、1、2或3個nt與AD-20807(SEQ ID ^[〇:5及6，或3£()1〇1^0:115及116)的反義股不同的至少 15個連續核苷酸。 在另一特定實施例中’ siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個nt與AD-20807之有義股不同的至 少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20807。 在另一特定實施例中’ siRNA具有由AD-20807之序列組 154740.doc -76· 201141489 成之序列。 在一特定實施例中，本發明包含具有反義股之RNAi 劑，該反義股包含有0、1、2或3個nt與AD-20826(SEQ ID NO: 43及44，或SEQ ID NO: 153及154)的反義股不同的至 少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個nt與AD-20826之有義股不同的至 φ 少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20826。 在另一特定實施例中，siRNA具有由AD-20626之序列組 成之序列。 在一特定實施例中，本發明包含具有反義股之RNAi 劑，該反義股包含有0、1、2或3個nt與AD-20832(其包含 SEQ ID NO: 55及 56，或 SEQ ID NO: 165及 166)的反義股不 同的至少15個連續核苷酸。 # 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個nt與AD-20832之有義股不同的至 少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20832。 在另一特定實施例中，siRNA具有由AD-20832之序列組 成之序列。 在一特定實施例中，本發明包含具有反義股之RNAi 劑，該反義股包含有0、1、2或3個nt與AD-20834(其包含 SEQ ID NO: 5 9及 60，或 SEQ ID NO: 169及 170)的反義股不 154740.doc •77- 201141489 同的至少15個連續核苷酸。 在另一特定實施例中’ siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個加與AD_2〇834之有義股不同的至 少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20834。 在另一特定實施例中，siRNA具有由AD-20834之序列組 成之序列。 在一特定實施例中，本發明包含具有反義股之RNAi 劑，該反義股包含有〇、1、2或3個nt與AD-20848(其包含 SEQ ID NO: 87及 88，或SEQ ID NO: 197 及 198)的反義股不 同的至少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個nt與AD-20848之有義股不同的至 少1 5個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20848。 在另一特定實施例中，siRNA具有由AD-20848之序列組 成之序列。 在一特定實施例中，本發明包含具有反義股之RNAi 劑，該反義股包含有〇、1、2或3個nt與AD-20861(其包含 SEQ ID NO: 97 及 98，或 SEQ ID NO:207 及 208)的反義股不 同的至少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或3個nt與AD-20861之有義股不同的至 少15個連續核苷酸。 154740.doc • 78 - 201141489 在另一特定實施例中，siRNA包含AD-20861。 在另一特定實施例中，siRNA具有由AD-20861之序列組 成之序列。 在一實施例中，本發明包含在10 nM活體外濃度下在 H441細胞中顯示β-ENaC基因至少約80%阻斷（不超過約 20%殘餘基因活性）的RNAi劑》 因此，在一特定實施例中，本發明包含具有反義股之 RNAi劑，該反義股包含有0、1、2或3個nt與AD-20832 ; AD-20848 ； AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 或AD-20834的反義股不同的至少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或 3個 nt 與 AD-20832 ; AD-20848 ; AD-20807 ; AD-20826 ; AD-20837 ; AD-20861 或 AD-20834 的 有義股不同的至少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20832 ; AD-20848 ; AD-20807 ; AD-20826 ； AD-20837 ； AD-20861 或 AD-20834。 在另一特定實施例中，siRNA具有由AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 或 AD-20834之序列組成的序列。 在一實施例中，本發明包含在10 nM活體外濃度下在 H441細胞中顯示β-ENaC基因至少約70%阻斷（不超過約 30%殘餘基因活性）的RNAi劑。 因此，在一特定實施例中，本發明包含具有反義股之 154740.doc -79- 201141489 RNAi劑，該反義股包含有0、l、2或3個nt與AD-2083 2; AD-20848 ； AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ；AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ; AD-20811 ； AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 或AD-20867的反義股不同的至少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或 3個 nt 與 AD-20832 ; AD-20848 ; AD-Minneapolis, October 14-17, 2009; or available as sc-42418 (and related products) from Santa Cruz Biotechnology, Santa Cruz, CA. Specific Examples of RNAi Agents for β-ENaC Various specific embodiments of RNAi agents for β-ENaC are disclosed herein. An example duplex sequence is provided herein and is for example set forth in Table 1. Particular embodiments of the invention include sequences comprising, for example, one, two or three nt or bp (e.g., 〇, 1, 2 or 3 mismatches) of the RNAi agents listed in Table 1 RNAi 154740.doc -75- 201141489 agent. A mismatch is defined herein as the difference between the maximum alignment of two sequences and the comparison of the sequence or length of the test base. A mismatch is defined as the position at which a base of one sequence does not match the base of another sequence. Thus, for example, if a position of a sequence has a particular base (e.g., A) and the corresponding position of another sequence has a different base (e.g., G), the mismatch is counted. For example, 'if a sequence has a base (eg, A), and the corresponding position of the other sequence does not have a base (eg, the position is a non-test nucleotide containing a phthalate-sugar backbone but no test) , then count the mismatch. A single incision in either sequence (or a positive or antisense strand) is not counted as a mismatch. Thus, as a non-limiting example, if a sequence contains the sequence AG, but another sequence contains the sequence AG and has a single-strand cut between A and G, the mismatch is not counted. The test-based modification is also not considered a mismatch. Thus, if a sequence contains c and another sequence contains a modified c (e.g., 2, _ modification) at the same position, the mismatch will not be counted. In a particular embodiment, 'the invention comprises an RNAi agent having an antisense strand' comprising 0, 1, 2 or 3 nt and AD-20807 (SEQ ID ^[〇: 5 and 6, or 3 The antisense strand of £()1〇1^0:115 and 116) differs by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the sense strand of AD-20807. In another specific embodiment, the siRNA comprises AD-20807. In another specific embodiment the 'siRNA has a sequence consisting of the sequence set of AD-20807 154740.doc -76· 201141489. In a specific embodiment, the invention comprises an RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20826 (SEQ ID NO: 43 and 44, or SEQ ID NO : 153 and 154) antisense strands differ by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising 〇, 1, 2 or 3 nt different from the sense strand of AD-20826 to 15 contiguous nucleotides to φ . In another specific embodiment, the siRNA comprises AD-20826. In another specific embodiment, the siRNA has a sequence consisting of the sequence of AD-20626. In a specific embodiment, the invention comprises an RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20832 comprising SEQ ID NOs: 55 and 56, or SEQ ID NO: The antisense strands of 165 and 166) differ by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the sense strand of AD-20832. In another specific embodiment, the siRNA comprises AD-20832. In another specific embodiment, the siRNA has a sequence consisting of the sequence of AD-20832. In a specific embodiment, the invention comprises an RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20834 comprising SEQ ID NOs: 5 9 and 60, or The antisense strands of SEQ ID NO: 169 and 170) are not 154740.doc • 77- 201141489 identical at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising at least 15 contiguous nucleotides different from the sense strand of AD 2 〇 834, 1、, 1, 2 or 3. In another specific embodiment, the siRNA comprises AD-20834. In another specific embodiment, the siRNA has a sequence consisting of the sequence of AD-20834. In a specific embodiment, the invention comprises an RNAi agent having an antisense strand comprising 〇, 1, 2 or 3 nt and AD-20848 comprising SEQ ID NOs: 87 and 88, or SEQ ID NO: The antisense strands of 197 and 198) differ by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the sense strand of AD-20848. In another specific embodiment, the siRNA comprises AD-20848. In another specific embodiment, the siRNA has a sequence consisting of the sequence of AD-20848. In a specific embodiment, the invention comprises an RNAi agent having an antisense strand comprising 〇, 1, 2 or 3 nt and AD-20861 comprising SEQ ID NO: 97 and 98, or SEQ ID NO: 207 and 208) differ in the antisense strand by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the sense strand of AD-20861. 154740.doc • 78 - 201141489 In another specific embodiment, the siRNA comprises AD-20861. In another specific embodiment, the siRNA has a sequence consisting of the sequence of AD-20861. In one embodiment, the invention comprises a RNAi agent that exhibits at least about 80% blockage (no more than about 20% residual gene activity) of the β-ENaC gene in H441 cells at an in vitro concentration of 10 nM. In an embodiment, the invention comprises a RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20832; AD-20848; AD-20807; AD-20826; AD-20837 The antisense strand of AD-20861 or AD-20834 differs by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising 〇, 1, 2 or 3 nt and AD-20832; AD-20848; AD-20807; AD-20826; AD- 20837; AD-20861 or AD-20834 has at least 15 contiguous nucleotides different from the sense strand. In another specific embodiment, the siRNA comprises AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861 or AD-20834. In another specific embodiment, the siRNA has a sequence consisting of the sequences of AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861 or AD-20834. In one embodiment, the invention comprises a RNAi agent that exhibits at least about 70% blockage (no more than about 30% residual gene activity) of the β-ENaC gene in H441 cells at an in vitro concentration of 10 nM. Thus, in a particular embodiment, the invention comprises a 154740.doc-79-201141489 RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-2083 2; AD- AD-20807 , AD-20826 , AD-20837 , AD-20861 , AD-20834 , AD-20806 , AD-20851 , AD-20865 , AD-20811 , AD-20819 , AD-20839 , AD-20835 ; The antisense strand of AD-20825 or AD-20867 differs by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA additionally comprises a sense strand comprising 〇, 1, 2 or 3 nt and AD-20832; AD-20848; AD-

20807 ； AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ； AD- 20819 ；AD-20839 ； AD-20835 ； AD-20825 或 AD-20867 的 有義股不同的至少15個連續核苷酸。 在另一特定實施例中，siRNA包含AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ；AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ^20-20; AD-20826; AD-20837; AD-20861; AD-20834; AD-20806; AD-20851; AD-20865; AD-20811; AD-20819; AD-20839; AD-20835; AD-20825 or The sense strand of AD-20867 differs by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA comprises AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861; AD-20834; AD-20806; AD-20851; AD-20865; AD-20811 ; AD-20819 ; AD-20839 ; AD-20835 ; AD-20825 ^

AD-20867。 在另一特定實施例中，siRNA具有由AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD- 20811 ；AD-20819 ； AD-20839 ; AD-20835 ； AD-20825 或 AD-20867之序列組成的序列。 在一實施例中，本發明包含在1 〇 nM活體外濃度下在 H441細胞中顯示β-ENaC基因至少約60%阻斷（不超過約 40%殘餘基因活性）的RNAi劑。 154740.doc -80 - 201141489 因此，在一特定實施例中，本發明包含具有反義股之 RNAi劑，該反義股包含有0、1、2或3個nt與AD-20832 ; AD-20848 ； AD-20807 ； AD-20826 ； AD-20837 ； AD-AD-20867. In another specific embodiment, the siRNA has AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861; AD-20834; AD-20806; AD-20851; AD-20865 AD-20811; AD-20819; AD-20839; AD-20835; Sequence of the sequence of AD-20825 or AD-20867. In one embodiment, the invention comprises a RNAi agent that exhibits at least about 60% blockage (no more than about 40% residual gene activity) of the β-ENaC gene in H441 cells at an in vitro concentration of 1 μM. 154740.doc -80 - 201141489 Accordingly, in a particular embodiment, the invention comprises a RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20832; AD-20848 AD-20807 ; AD-20826 ; AD-20837 ; AD-

20861 ；AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-2081 1 ； AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ；AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-20831 ; AD-20862 ; AD-20808或 AD-20827的反義股不 同的至少15個連續核苷酸。 另一特定實施例中，siRNA亦另外包含有義股，該有義 股包含有 〇、1、2或 3個 nt 與 AD-20832 ; AD-20848 ; AD-20807 ; AD-20826 ； AD-20837 ; AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ； AD- 20819 ；AD-20839 ； AD-20835 ； AD-20825 ; AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-20831 ； AD- 20862 ; AD-20808或AD-20827的有義股不同的至少15個連 續核苷酸β 在另一特定實施例中，siRNA包含AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD- 20811 ；AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ； AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD- 20831 ; AD-20862 ; AD-20808 或 AD-20827。 在另一特定實施例中，siRNA具有由AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ； 154740.doc -81 · 201141489 AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ；AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ； AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-20831 ; AD-20862 ; AD-20808 或 AD-20827 之序歹丨J 組成的序 列。20861 ; AD-20834 ; AD-20806 ; AD-20851 ; AD-20865 ; AD-2081 1 ; AD-20819 ; AD-20839 ; AD-20835 ; AD-20825 ; AD-20867 ; AD-20813 ; AD-20823 AD-20805 ; AD-20831 ; AD-20862 ; AD-20808 or AD-20827 have at least 15 contiguous nucleotides different from the antisense strand. In another specific embodiment, the siRNA additionally comprises a sense strand comprising 〇, 1, 2 or 3 nt and AD-20832; AD-20848; AD-20807; AD-20826; AD-20837 AD-20861 ; AD-20834 ; AD-20806 ; AD-20851 ; AD-20865 ; AD-20811 ; AD-20819 ; AD-20839 ; AD-20835 ; AD-20825 ; AD-20867 ; AD-20813 ; -20823; AD-20805; AD-20831; AD-20862; at least 15 contiguous nucleotides of the sense strand of AD-20808 or AD-20827. In another specific embodiment, the siRNA comprises AD-20832; AD-20848 AD-20826 AD-20837 AD-20861 AD-20834 AD-20806 AD-20851 AD-20865 AD-18811 AD-20819 AD-20839 AD- 20835; AD-20825; AD-20867; AD-20813; AD-20823; AD-20805; AD-20831; AD-20862; AD-20808 or AD-20827. In another specific embodiment, the siRNA has AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861; 154740.doc-81.201141489 AD-20834; AD-20806; AD-20851 AD-20811 AD-20819 AD-20839 AD-20835 AD-20825 AD-20867 AD-20813 AD-20823 AD-20805 AD-20831 AD- 20862; Sequence of the sequence 歹丨J of AD-20808 or AD-20827.

在一實施例中，本發明包含在1 0 nM活體外濃度下在 H441細胞中顯示β-ENaC基因至少約50%阻斷（不超過約 50%殘餘基因活性）的RNAi劑。 因此，在一特定實施例中，本發明包含具有反義股之 RNAi劑，該反義股包含有0、1、2或3個nt與AD-20832 ; AD-20848 ； AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ；AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ； AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ；AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ；In one embodiment, the invention comprises a RNAi agent that exhibits at least about 50% blockage (no more than about 50% residual gene activity) of the β-ENaC gene in H441 cells at an in vitro concentration of 10 nM. Thus, in a particular embodiment, the invention comprises a RNAi agent having an antisense strand comprising 0, 1, 2 or 3 nt and AD-20832; AD-20848; AD-20807; AD- AD8261 , AD-20861 , AD-20834 , AD-20806 , AD-20851 , AD-20865 , AD-20811 , AD-20819 , AD-20839 , AD-20835 , AD-20825 , AD-20867 ; AD-20813 ; AD-20823 ; AD-20805 ;

AD-2083 1 ； AD-20862 ； AD-20808 ； AD-20827 ； AD-20828 ；AD-20812 ; AD-20836 或 D-20822 的反義股不同的 至少15個連續核苷酸。 在另一特定實施例中，siRNA亦另外包含有義股，該有 義股包含有〇、1、2或 3個 nt 與 AD-20832 ; AD-20848 ; AD-20807 ; AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD-20811 ； AD-20819 ；AD-20839 ； AD-20835 ； AD-20825 ； AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-2083 1 ； AD-20862 ；AD-20808 ； AD-20827 ； AD-20828 ； AD-20812 ； 154740.doc -82- 201141489 AD-20836或AD-20822的有義股不同的至少15個連續核苷 酸。 在另一特定實施例中，siRNA包含AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ; AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD- 20811 ；AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ； AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-AD-2083 1 ; AD-20862 ; AD-20808 ; AD-20827 ; AD-20828 ; AD-20812 ; AD-20836 or D-20822 have at least 15 contiguous nucleotides different in antisense strands. In another specific embodiment, the siRNA additionally comprises a sense strand comprising 〇, 1, 2 or 3 nt and AD-20832; AD-20848; AD-20807; AD-20826; AD- AD-20861 AD-20834 AD-20806 AD-20851 AD-20865 AD-20811 AD-20819 AD-20839 AD-20835 AD-20825 AD-20867 AD-20813 ; AD-20823 ; AD-20805 ; AD-2083 1 ; AD-20862 ; AD-20808 ; AD-20827 ; AD-20828 ; AD-20812 ; 154740.doc -82- 201141489 AD-20836 or AD-20822 The strands differ by at least 15 contiguous nucleotides. In another specific embodiment, the siRNA comprises AD-20832; AD-20848; AD-20807; AD-20826; AD-20837; AD-20861; AD-20834; AD-20806; AD-20851; AD-20865; AD-20811 ; AD-20819 ; AD-20839 ; AD-20835 ; AD-20825 ; AD-20867 ; AD-20813 ; AD-20823 ; AD-20805 ;

20831 ；AD-20862 ； AD-20808 ； AD-20827 ； AD-20828 ； AD-20812 ; AD-20836或 AD-20822 » 在另一特定實施例中，siRNA具有由AD-20832 ; AD-20848 ; AD-20807 ； AD-20826 ； AD-20837 ； AD-20861 ； AD-20834 ； AD-20806 ； AD-20851 ； AD-20865 ； AD- 20811 ；AD-20819 ； AD-20839 ； AD-20835 ； AD-20825 ； AD-20867 ； AD-20813 ； AD-20823 ； AD-20805 ； AD-20831 ；AD-20862 ； AD-20808 ； AD-20827 ； AD-20828 ； AD-20812 ; AD-20836或AD-20822之序列組成之序列。 針對P-ENaC之RNAi劑的多個實施例 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20805之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20806之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 154740.doc -83- 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、i、2或3個以與AD_2〇8〇7之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少丨5個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個加與AD_2〇8〇82 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20809之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20810之 有義股不同的至少1 5個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20811之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20812之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 154740.doc • 84· 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20813之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20814之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一貫施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20815之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、i、2或3個nt與AD-20816之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少丨5個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有0、1、2或3個…與AD_2〇817之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、卜2或3個以與AD_2〇81k 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 154740.doc -85 - 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20819之 有義股不同的至少丨5個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20820之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20821之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20822之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20823之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個n^AD-2〇824之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 154740.doc • 86 - 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20825之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20826之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸β 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20827之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20828之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20829之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1 ' 2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20830之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 154740.doc • 87· 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20831之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、i、2或3個肘與ad-20832之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苦酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20833之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核;酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、i、2或3個价與八〇-20834之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、i、2或3個n^AD-20835之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苦酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20836之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 I54740.doc •88· 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-2083 7之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20838之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20839之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20840之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸》 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20841之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20842之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 154740.doc •89- 201141489 1、2或3個nt與其反義股不同的至少15個連續核苦酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20843之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有0、1、2或3個nt與AD-20844之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20845之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20846之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD-20847之 有義股不同的至少15個連續核苷酸，該反義股包含有0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20848之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 154740.doc •90· 201141489 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑’該有義股包含有〇、1、2或3個加與AD2〇849之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中’本發明包含具有有義股及/或反義股 2RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20850 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 2RNAl劑’該有義股包含有0、1、2或3個nt與AD-20851 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 之RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20852 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇 ' 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 之⑽八丨劑’該有義股包含有0、1、2或3個nt與AD-20861 之有義股不同的至少丨5個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 之⑽八1劑’該有義股包含有〇、1、2或3個nt與AD-20862 之有義股不同的至少15個連續核苷酸，該反義股包含有 154740.doc •91 · 201141489 0、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 之RNAi劑’該有義股包含有〇、1、2或3個nt與AD-20863 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中’本發明包含具有有義股及/或反義股 之RNAi劑，該有義股包含有〇、1、2或3個以與ad-20864 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明包含具有有義股及/或反義股 之RNAi劑，該有義股包含有〇、1、2或3個以與ad-20865 之有義股不同的至少15個連續核苷酸，該反義股包含有 〇、1、2或3個nt與其反義股不同的至少15個連續核苷酸。 在一實施例中’本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個nt與AD_2〇866i 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、 2或3個nt與其反義股不同的至少丨5個連續核苷酸。 在一實施例中，本發明包含具有有義股及/或反義股之 RNAi劑，該有義股包含有〇、1、2或3個以與ad-20867之 有義股不同的至少15個連續核苷酸，該反義股包含有〇、 1、2或3個nt與其反義股不同的至少15個連續核苷酸。 針對p-ENaC之RNAi劑的多個實施例 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 154740.doc -92- 201141489 苷酸與AD-20805(其包含SEQ ID NO. 111-112及其經修飾 變異體）之反義股不同的至少15個連續核苷酸》 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20806(其包含SEQ ID NO· 113-114及其經修飾 變異體）之反義股不同的至少1 5個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20807(其包含SEQ ID NO. 115-116及其經修都 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20808(其包含SEQ ID NO. 117-118及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20809(其包含SEQ ID NO· 119-120及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20810(其包含SEQ ID NO. 121-122及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc -93· 201141489 苷酸與AD-20811(其包含SEQ ID NO. 123-124及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20812(其包含SEQ ID NO. 125-126及其經修傳 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、i、2或3個核 苷酸與AD-20813(其包含SEQ ID NO. 127-128及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20814(其包含SEQ ID NO. 129-130及其經修辦 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20815(其包含SEQ ID NO. 131-132及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苦酸與AD_20816(其包含SEQ ID NO. 133-134及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc -94· 201141489 苷酸與AD-20817(其包含SEQ ID NO. 135-136及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20818(其包含SEQ ID NO. 137-138及其經修飾 變異體）之反義股不同的至少15個連續核苷酸》 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20819(其包含SEQ ID NO. 139-140及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20820(其包含SEQ ID NO. 141-142及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有0、1、2或3個核 苷酸與AD-20821(其包含SEQ ID NO. 143-144及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20822(其包含SEQ ID NO. 145-146及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc -95- 201141489 苷酸與AD-20823(其包含SEQ ID NO· 147-148及其經修錦 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、i、2或3個核 苷酸與AD-20824(其包含SEQ ID NO. 149-150及其經修飾 變異體）之反義股不同的至少丨5個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20825(其包含SEQ ID NO. 151-152及其經修斜 變異體）之反義股不同的至少丨5個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20826(其包含SEQ ID NO. 153-154及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20827(其包含SEq ID NO. 155-156及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAl劑的組合物’其中反義股包含有0、1、2或3個核 苦酸與AD-20828(其包含SEq ID NO. 157-158及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc 201141489 苷酸與AD-20829(其包含SEQ ID NO· 159-160及其經修錦 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20830(其包含SEQ ID NO· 161-162及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20831(其包含SEQ ID NO· 163-164及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20832(其包含SEQ ID NO. 165-166及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20833(其包含SEQ ID NO. 167-168及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20834(其包含SEQ ID NO. 169-170及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 154740.doc •97- 201141489 苷酸與AD-20835(其包含SEQ ID NO. 171-172及其經修都 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20836(其包含SEQ ID NO· 173-174及其經修舞 變異體）之反義股不同的至少15個連續核苷酸。 在一貫施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、}、2或3個核 苷酸與AD-20837(其包含SEQ ID NO. 175-176及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、！、2或3個核 苷酸與AD-20838(其包含SEQ ID NO. 177-178及其經修舞 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1'2或3個核 苷酸與AD-20839(其包含SEQ ID NO. 179-180及其經修韵j 變異體）之反義股不同的至少15個連續核苦酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20840(其包含SEQ ID NO. 181-182及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc -98- 201141489 苷酸與AD-20841(其包含SEQ ID NO. 183-184及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有0、1、2或3個核 苷酸與AD-20842(其包含SEQ ID NO. 185-186及其經修飾 變異體）之反義股不同的至少1 5個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD_20843(其包含SEQ ID NO. 187-188及其經修飾 變異體）之反義股不同的至少1 5個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20844(其包含SEQ ID NO_ 189-190及其經修飾 變異體）之反義股不同的至少1 5個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20845(其包含SEQ ID NO· 191-192及其經修飾 變異體）之反義股不同的至少1 5個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20846(其包含SEQ ID NO. 193-194及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 154740.doc -99· 201141489 苷酸與AD-20847(其包含SEQ ID NO. 195-196及其經修饰 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中’本發明係關於包含具有有義股及反義股 之RNAi劑的組合物’其中反義股包含有〇、1、2或3個核 苷酸與AD-20848(其包含SEq ID NO. 197-198及其經修飾 變異體）之反義股不同的至少丨5個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1χ243個核 苦酸與AD-20849(其包含SEq ID NO. 199-200及其經修饰 變異體）之反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明係關於包含有義股及反義股之 RNAi劑的組合物，其中反義股包含有〇、1、2或3個核苷 酸與AD-20850(其包含SEQ ID NO. 201-202及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在一個實施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物，其中反義股包含有〇、1、2或3個核苷 1與八〇-20851(其包含SEq ID N〇 2〇32〇4及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在個貫施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物’其中反義股包含有〇、1、之或]個核苷 l”AD-2〇852(其包含seq id NO. 205-206及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在個貫施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物’其中反義股包含有〇、1、2或3個核苷 154740.doc 201141489 酸與AD-20861(其包含SEQ ID NO. 207-208及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在一個實施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物，其中反義股包含有〇、1、2或3個核苷 酸與AD-20862(其包含SEQ ID NO. 209-210及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在一個實施例中，本發明係關於包含有義股及反義股之 RNAi劑的組合物’其中反義股包含有〇、1、2或3個核苷 酸與AD-20863(其包含SEQ ID NO· 211-212及其經修飾變 異體）之反義股不同的至少15個連續核普酸》 在一個實施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物’其中反義股包含有〇、1、2或3個核皆 酸與AD-20864(其包含SEQ ID NO. 213-214及其經修娜變 異體）之反義股不同的至少15個連續核苷酸。 在一個實施例中’本發明係關於包含有義股及反義股之 RNAi劑的組合物’其中反義股包含有〇、1、2或3個核苦 酸與AD-20865(其包含SEQ ID NO. 215-216及其經修飾變 異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 苷酸與AD-20866(其包含SEQ ID NO. 217-218及其經修部 變異體）之反義股不同的至少15個連續核苷酸。 在一實施例中，本發明係關於包含具有有義股及反義股 之RNAi劑的組合物，其中反義股包含有〇、1、2或3個核 154740.doc •101 - 201141489 苷酸與AD-20867(其包含SEQ ID NO. 219-220及其經修飾 變異體）之反義股不同的至少15個連續核苷酸。 針對p-ENaC之RNAi劑的多個實施例 在一實施例中’組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與ad-20805(其 包含SEQ ID NO. 111及112)之反義股不同的至少15個連續 核苷酸。 在一實施例中’組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20806(其 包含SEQ ID NO. 113及114)之反義股不同的至少15個連續 核苷酸》 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與ad_20807(其 包含SEQ ID NO_ 115及116)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與ad_20808(其 包含SEQ ID NO. 117及118)之反義股不同的至少15個連續 核普酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20809(其 包含SEQ ID NO. 119及120)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -102- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20810(其 包含SEQ ID NO. 121及122)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20811(其 包含SEQ ID NO. 123及124)之反義股不同的至少15個連續 核普酸。 φ 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20812(其 包含SEQ ID NO. 125及126)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20813(其 包含SEQ ID NO. 127及128)之反義股不同的至少15個連續 核苷酸。 # 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20814(其 包含SEQ ID NO. 129及130)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20815(其 包含SEQ ID NO. 131及132)之反義股不同的至少15個連續 核苷酸》 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -103- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20816(其 包含SEQ ID NO. 133及134)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20817(其 包含SEQ ID NO. 13 5及13 6)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20818(其 包含SEQ ID NO. 13 7及13 8)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20819(其 包含SEQ ID NO. 139及140)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20820(其 包含SEQ ID NO. 141及142)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20821(其 包含SEQ ID NO. 143及144)之反義股不同的至少I5個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc •104· 201141489 RNAi劑，其中該反義股包含有0個核苷酸與AD-20822(其 包含SEQ ID NO. 145及146)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20823(其 包含SEQ ID NO. 147及148)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20824(其 包含SEQ ID NO. 149及150)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20825(其 包含SEQ ID NO. 151及152)之反義股不同的至少15個連續 核苷酸。 在一實施例中’組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與ad_20826(其 包含SEQ ID NO. 153及15 4)之反義股不同的至少15個連續 核苷酸》 在一實施例中’組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核皆酸與ad-2 〇827(其 包含SEQ ID NO. I55及156)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -105- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20828(其 包含SEQ ID NO. 157及15 8)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20829(其 包含SEQ ID NO. 159及160)之反義股不同的至少15個連續 核皆酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20830(其 包含SEQ ID NO. 161及162)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20831(其 包含SEQ ID NO. 163及164)之反義股不同的至少15個連續 核普酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20832(其 包含SEQ ID NO. 165及166)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20833(其 包含SEQ ID NO. 167及168)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -106- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20834(其 包含SEQ ID NO. 169及17〇)之反義股不同的至少15個連續 核苷酸^ 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20835(其 包含SEQ ID NO. 171及172)之反義股不同的至少15個連續 核苷酸。 φ 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20836(其 包含SEQ ID NO. 173及174)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20837(其 包含SEQ ID NO_ 175及176)之反義股不同的至少15個連續 核苷酸。 # 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20838(其 包含SEQ ID NO. 177及178)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20839(其 包含SEQ ID NO. 179及180)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc •107- 201141489 RNAi劑，其中該反義股包含有0個核苷酸與AD-20840(其 包含SEQ ID NO. 181及182)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20841(其 包含SEQ ID NO. 183及184)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20842(其 包含SEQ ID NO. 185及186)之反義股不同的至少15個連續 核普酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20843(其 包含SEQ ID NO. 187及188)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20844(其 包含SEQ ID NO. 189及190)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20845(其 包含SEQ ID NO. 191及192)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc •108· 201141489 RNAi劑，其中該反義股包含有0個核苷酸與AD-20846(其 包含SEQ ID NO. 193及194)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20847(其 包含SEQ ID NO. 195及196)之反義股不同的至少15個連續 核苦酸。 φ 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20848(其 包含SEQ ID NO. 197及198)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20849(其 包含SEQ ID NO. 199及200)之反義股不同的至少15個連續 核苦酸。 # 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20850(其 包含SEQ ID NO. 201及202)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有0個核苷酸與AD-20851(其 包含SEQ ID NO. 203及204)之反義股不同的至少15個連續 核苦酸。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -109- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20852(其 包含SEQ ID NO. 205及206)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑’其中該反義股包含有〇個核苷酸與AD-20861(其 包含SEQ ID NO. 207及208)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20862(其 包含SEQ ID NO. 209及210)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20863(其 包含SEQ ID NO. 211及212)之反義股不同的至少15個連續 核苷酸。 在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與ad_20864(其 包含SEQ ID NO. 213及214)之反義股不同的至少15個連續 核苷酸。 在一實施例中’組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與ad-20865(其 包含SEQ ID NO. 215及216)之反義股不同的至少15個連續 核苷酸’。 在一實施例中，組合物包含具有有義股及反義股之 154740.doc -110- 201141489 RNAi劑，其中該反義股包含有〇個核苷酸與AD-20866(其 包含SEQ ID NO. 217及218)之反義股不同的至少15個連續 核苷酸。 且在一實施例中，組合物包含具有有義股及反義股之 RNAi劑，其中該反義股包含有〇個核苷酸與ad_20867(其 包含SEQ ID NO. 219及220)之反義股不同的至少15個連續 核苷酸。 針對P-ENaC之RNAi劑的多個實施例 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20805(包含SEQ ID NO. 1及2)的反 義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20806(包含SEQ ID NO. 3及4)的反 義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與ad_20807(包含SEQ ID NO. 5及6)的反 義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與ad-20808(包含SEQ ID NO. 7及8)的反 義序列不同的至少15個連續核苷酸。 154740.doc 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20809(包含SEQ ID NO. 9及10)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20810(包含SEQ ID NO. 11及12)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20811(包含SEQ ID NO. 13及14)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20812(包含SEQ ID NO. 15及16)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20813(包含SEQ ID NO· 17及18)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20814(包含SEQ ID NO· 19及20)的 反義序列不同的至少15個連續核苷酸。 154740.doc 112- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20815(包含SEQ ID NO. 21及22)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20816(包含SEQ ID NO. 23及24)的 # 反義序列不同的至少15個連續核苷酸》 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20817(包含SEQ ID NO. 25及26)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20818(包含SEQ ID NO. 27及28)的 • 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20819(包含SEQ ID NO. 29及30)的 反義序列不同的至少15個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20820(包含SEQ ID NO. 31及32)的 反義序列不同的至少15個連續核苷酸。 154740.doc -113- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20821(包含SEQ ID NO. 33及34)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20822(包含SEQ ID NO. 35及36)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20823(包含SEQ ID NO. 37及38)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20824(包含SEQ ID NO. 39及40)的 反義序列不同的至少15個連續核苷破。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20825(包含SEQ ID NO. 41及42)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20826(包含SEQ ID NO. 43及44)的 反義序列不同的至少15個連續核苷酸。 154740.doc 114 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20827(包含SEQ ID NO. 45及46)的 反義序列不同的至少丨5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與aD_2〇828(包含SEQ ID NO. 47及48)的 φ 反義序列不同的至少15個連續核苷酸。 在一貫施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與ad-20829(包含SEQ ID NO. 49及50)的 反義序列不同的至少丨5個連續核苷酸。 在一實施例中，組令物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與aD_2〇830(包含SEQ ID NO. 51及52)的 • 反義序列不同的至少1 5個連續核苷酸。 在一貫施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD_2〇831(包含SEQ⑴N〇 53及54)的 反義序列不同的至少1 5個連續核苷酸。 在貫施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD_2〇832(包含SEQ ID N〇 55及56)的 反義序列不同的至少15個連續核苷酸。 154740.doc -115- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20833(包含SEQ ID NO· 57及58)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20834(包含SEQ ID NO. 59及60)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-2083 5(包含SEQ ID NO. 61及62)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20836(包含SEQ ID NO. 63及64)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20837(包含SEQ ID NO. 65及66)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20838(包含SEQ ID NO. 67及68)的 反義序列不同的至少15個連續核苷酸。 154740.doc -116- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20839(包含SEQ ID NO. 69及70)的 反義序列不同的至少15個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20840(包含SEQ ID NO. 71及72)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20841(包含SEQ ID NO. 73及74)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20842(包含SEQ ID NO. 75及76)的 反義序列不同的至少15個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1 ' 2或3個核苷酸與AD-20843(包含SEQ ID NO. 77及78)的 反義序列不同的至少15個連續核苷酸。 在一實施例中’組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20844(包含SEQ ID NO. 79及80)的 反義序列不同的至少15個連續核苦酸。 154740.doc -117- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20845(包含SEQ ID NO_ 81及82)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20846(包含SEQ ID NO. 83及84)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20847(包含SEQ ID NO. 85及86)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20848(包含SEQ ID NO. 87及88)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20849(包含SEQ ID NO. 89及90)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修姊變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20850(包含SEQ ID Ν〇· 91及92)的 反義序列不同的至少1 5個連續核苷酸。 I54740.doc -118- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體’ 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20851(包含SEQ ID NO. 93及94)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或3個核苷酸與AD-20852(包含SEQ ID NO. 95及96)的 反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20861(包含SEQ ID NO. 97及98)的 反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD-20862(包含SEQ ID NO. 99及100) 的反義序列不同的至少15個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD_2〇863(包含SEQ ID N〇 1〇1及1〇2) 的反義序列不同的至少15個連續核苷酸。 在貫把例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與AD_2〇864(包含SEQ出ν〇 1〇3及1〇4) 的反義序列不同的至少丨5個連續核苷酸。 154740.doc -119- 201141489 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或 3個核苷酸與 AD-20865(包含 SEQ ID NO. 105 及 106) 的反義序列不同的至少1 5個連續核苷酸。 在一實施例中，組合物包含RNAi劑之經修飾變異體， 其中變異體包含有義股及反義股，其中反義股包含有0、 1、2或 3個核苷酸與 AD-20866(包含 SEQ ID NO. 107 及 108) 的反義序列不同的至少15個連續核苷酸。 且在一實施例中，組合物包含RNAi劑之經修飾變異 體，其中變異體包含有義股及反義股，其中反義股包含有 0、1、2或3個核苷酸與AD-20867(包含SEQ ID NO. 109及 110)的反義序列不同的至少15個連續核苷酸。 針對p-ENaC之RNAi劑的多個實施例 在一實施例中，本發明包含AD-20805(SEQ ID NO: 1及 2，或SEQ ID NO: 111 及 112)。 在一實施例中，本發明包含AD-20806(SEQ ID NO: 3及 4，或 SEQ ID NO: 113及 114)。 在一實施例中，本發明包含AD-20807(SEQ ID NO: 5及 6，或 SEQ ID NO: 115及 116)。 在一實施例中，本發明包含AD-20808(SEQ ID NO: 7及 8，或 SEQ ID NO: 11 7及 118)。 在一實施例中，本發明包含AD-20809(SEQ ID NO: 9及 10，或 SEQ ID NO: 119及 120)。 在一實施例中，本發明包含AD-20810(SEQ ID NO: 11及 154740.doc •120· 201141489 12，或 SEQ ID NO: 121 及 122)。 在一實施例中，本發明包含AD-20811 (SEQ ID NO: 13及 14，或 SEQ ID NO: 123及 124)。 在一實施例中，本發明包含AD-20812(SEQ ID NO: 15及 16，或 SEQ ID NO: 125及 126)。 在一實施例中，本發明包含AD-20813(SEQ ID NO: 17及 18，或 SEQ ID NO: 127及 128)。 在一實施例中，本發明包含AD-20814(SEQ ID NO: 19及 20，或 SEQ ID NO: 129及 13 0)。 在一實施例中，本發明包含AD_20815(SEQ ID NO: 21及 22，或 SEQ ID NO: 131及 132)。 在一實施例中，本發明包含AD-20816(SEQ ID NO: 23及 24，或 SEQ ID NO: 133及 134)。 在一實施例中，本發明包含ad-2〇817(SEQ ID NO: 25及 26，或 SEQ ID NO: 135及 136)。 φ 在一實施例中，本發明包含AD-20818(SEQ ID NO: 27及 28，或 SEQ ID NO: 137及 13 8)。 在一實施例中’本發明包含AD_2〇819(SEQ ID NO: 29及 30，或 SEQ ID NO: 139及 140)。 在一實施例中，本發明包含AD-20820(SEQ ID NO: 31及 32，或 SEQ ID NO: 141 及 142)。 在一實施例中，本發明包含AD-2〇821 (SEQ ID NO·· 33及 34，或 SEQ ID NQ: 143及 144)。 在一實施例中，本發明包含八〇-2〇822(8£(^1〇]^0:3 5及 154740.doc -121 - 201141489 36，或 SEQ ID NO: 145及 146)。 在一實施例中，本發明包含八〇-20823(8£(^1〇1^〇:3 7及 38，或 SEQ ID NO: 147及 148)。 在一實施例中，本發明包含AD-20824(SEQ ID NO: 39及 40，或 SEQ ID NO: 149及 15 0)。 在一實施例中，本發明包含AD-20825(SEQ ID NO: 41及 42，或 SEQ ID NO: 151及 152)。 在一實施例中，本發明包含AD-20826(SEQ ID NO: 43及 44，或 SEQ ID NO: 153及 154)。 在一實施例中，本發明包含AD-20827(SEQ ID NO: 45及 46，或 SEQ ID NO: 155及 156)。 在一實施例中，本發明包含AD-20828(SEQ ID NO: 47及 48，或 SEQ ID NO: 157及 15 8)。 在一實施例中，本發明包含AD-20829(SEQ ID NO: 49及 50，或 SEQ ID NO: 159及 160)。 在一實施例中，本發明包含AD-20830(SEQ ID NO: 51及 52，或 SEQ ID NO: 161 及 162)。 在一實施例中，本發明包含AD-2083 1 (SEQ ID NO: 53及 54，或 SEQ ID NO: 163及 164)。 在一實施例中，本發明包含AD-20832(SEQIDNO:5 5及 56，或 SEQ ID NO: 165及 166)。 在一實施例中，本發明包含AD-20833(SEQ ID NO: 57及 58，或 SEQ ID NO: 167及 168)。 在一實施例中，本發明包含AD-20834(SEQ ID NO: 59及 154740.doc •122· 201141489 60，或 SEQ ID NO: 169及 170)。 在一實施例中，本發明包含AD-20835(SEQ ID NO: 61及 62，或 SEQ ID NO: 171 及 172)。 在一實施例中，本發明包含AD-20836(SEQ ID NO: 63及 64，或 SEQ ID NO: 173及 174)。 在一實施例中，本發明包含AD-20837(SEQ ID NO: 65及 66，或 SEQ ID NO: 175及 176)。 • 在一實施例中，本發明包含AD-20838(SEQ ID NO: 67及 68，或 SEQ ID NO: 177及 178)。 在一實施例中，本發明包含AD-20839(SEQ ID NO: 69及 70，或 SEQ ID NO: 179及 180)。 在一實施例中，本發明包含AD-20840(SEQ N0: 71及 72，或 SEQ ID NO: 181及 182)。 在一實施例中，本發明包含AD-20841 (SEQ ID NO: 73及 74，或 SEQ ID NO: 183及 184)。 在一實施例中，本發明包含AD-20842(SEQ ID NO: 75及 76，或 SEQ ID NO: 185及 186)。 在一實施例中，本發明包含AD_2〇843(SEQ ID NO: 77及 78，或 SEQ ID NO: 187及 188)。 在一實施例中，本發明包含AD_2〇844(SEQ ID NO: 79及 80，或 SEQ ID NO: 189及 190)。 在一實施例中，本發明包含AD-20845 (SEQ ID NO: 8 1及 82，或 SEQ ID NO: 191 及 192)。 在一實施例中，本發明包含AD-20846(SEQ ID NO: 83及 154740.doc -123- 201141489 84，或 SEQ ID NO: 193及 194)。 在一實施例中，本發明包含AD-20847(SEQ ID NO: 85及 86，或 SEQ ID NO: 195及 196)。 在一實施例中，本發明包含AD-20848(SEQ ID NO: 87及 88，或 SEQ ID NO: 197及 198)。 在一實施例中，本發明包含AD-20849(SEQ ID NO: 89及 90，或 SEQ ID NO: 199及 200)。 在一實施例中，本發明包含AD-2085 0(SEQ ID NO: 91及 92，或 SEQ ID NO: 201 及 202)。 在一實施例中，本發明包含AD-20851 (SEQ ID NO: 93及 94，或 SEQ ID NO: 203及 204)。 在一實施例中，本發明包含AD-20852(SEQ ID NO: 95及 96，或 SEQ ID NO: 205及 206)。 在一實施例中，本發明包含AD-20861(SEQ ID NO: 97及 98，或 SEQ ID NO: 207及 208)。 在一實施例中，本發明包含AD-20862(SEQ ID NO: 99及 100，或 SEQ ID NO: 209及 210)。 在一實施例中，本發明包含AD-20863(SEQ ID NO: 101 及 102，或 SEQIDNO:211 及 212)。 在一實施例中，本發明包含AD-20864(SEQ ID NO: 103 及 104，或 SEQIDNO:213 及 214)。 在一實施例中，本發明包含AD-20865(SEQ ID NO: 105 及 106，或 SEQIDNO:215 及 216)。 在一實施例中，本發明包含AD-20866(SEQ ID NO: 107 154740.doc -124· 201141489 及 108，或 SEQIDNO:217 及 218)。 在一實施例中，本發明包含AD-20867(SEQ ID NO: 109 及 110，或 SEQ ID NO: 219及 220)。 在一實施例中，RNAi劑包含為AD-20805之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20806之反義股的確 切序列及長度的反義股。 φ 在一實施例中，RNAi劑包含為AD-20807之反義股的確 切序列及長度的反義股》 在一實施例中，RNAi劑包含為AD-20808之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20809之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20810之反義股的確 切序列及長度的反義股。 • 在一實施例中，RNAi劑包含為AD-20811之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-208 12之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-208 13之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20814之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20815之反義股的確 154740.doc -125- 201141489 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20816之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20817之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-2081 8之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20819之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20820之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20821之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20822之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20823之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20824之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20825之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20826之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20827之反義股的確 154740.doc -126- 201141489 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20828之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20829之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20830之反義股的確 切序列及長度的反義股。 φ 在一實施例中，RNAi劑包含為AD-20831之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20832之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20833之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20834之反義股的確 切序列及長度的反義股。 • 在一實施例中，RNAi劑包含為AD-20835之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20836之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20837之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20838之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20839之反義股的確 154740.doc -127- 201141489 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20840之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20841之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20842之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20843之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20844之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20845之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20846之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20847之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20848之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20849之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20850之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20851之反義股的確 154740.doc -128- 201141489 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20852之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20861之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20862之反義股的確 切序列及長度的反義股。 φ 在一實施例中，RNAi劑包含為AD-20863之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20864之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20865之反義股的確 切序列及長度的反義股。 在一實施例中，RNAi劑包含為AD-20866之反義股的確 切序列及長度的反義股。 # 在一實施例中，RNAi劑包含為AD-20867之反義股的確 切序列及長度的反義股。在此等多個實施例中，包含為所 述RNAi劑之所述反義股的確切序列及長度的反義股之 RNAi劑可包含經修飾核苷酸、3'端帽端及/或不改變RNAi 劑之序列或長度的其他修飾。 針對p-ENaC之RNAi劑的多個實施例 在一實施例中，RNAi劑包含由與AD-20805之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20806之反義股序 154740.doc -129- 201141489 列具有ο、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20807之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20808之反義股序 列具有0、1、2或3個錯配之序列組,成之反義股。 在一實施例中，RNAi劑包含由與AD-20809之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20810之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20811之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20812之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20813之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20814之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20815之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20816之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20817之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20818之反義股序 154740.doc -130- 201141489 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20819之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20820之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20821之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20822之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20823之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20824之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20825之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20826之反義股序 列具有0、1、2或3個錯配之序列组成之反義股。 在一實施例中’ RNAi劑包含由與AD-20827之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20828之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20829之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一貫施例中’ RNAi劑包含由與AD-20830之反義股序 154740.doc -131 - 201141489 列具有ο、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20831之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20832之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20833之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20834之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20835之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20836之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20837之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20838之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20839之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20840之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20841之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20842之反義股序 154740.doc -132· 201141489 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20843之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20844之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20845之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 鲁在一實施例中，RNAi劑包含由與AD-20846之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20847之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20848之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與AD-20849之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 鲁 在一實施例中’ RNAi劑包含由與AD-20850之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與Ad_20851之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中’ RNAi劑包含由與ad-20852之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20861之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與ad-20862之反義股序 154740.doc -133· 201141489 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20863之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20864之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20865之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20866之反義股序 列具有0、1、2或3個錯配之序列組成之反義股。 在一實施例中，RNAi劑包含由與AD-20867之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股。 針對P-ENaC之RNAi劑的多個實施例 在一實施例中，RNAi劑包含由與AD-20805之反義股序 列具有〇、1、2或3個錯配之序列組成的反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍，例如0-1、1-2、1-3、1-4、1-5、1-6、1-7、1-8、1-9、1-10、2-3、2-4 或 2-5個 nt等）。 在一實施例中，RNAi劑包含由與AD-20806之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20807之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 154740.doc •134- 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20808之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20809之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20810之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20811之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5' 6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20812之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20813之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 154740.doc -135- 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與ad_20814之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中’ RNAi劑包含由與AD-208 15之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-208 16之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20817之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5'6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-208 18之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20819之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反.義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 154740.doc -136- 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20820之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 k視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20821之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20822之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20823之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1 〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20824之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20825之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 154740.doc -137· 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20826之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20827之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20828之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20829之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20830之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）》 在一實施例中，RNAi劑包含由與AD-20831之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 154740.doc •138· 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20832之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20833之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 φ 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20834之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20835之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 Φ 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20836之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20837之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 154740.doc -139· 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20838之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 月又視情況另外包含〇、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20839之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8'9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20840之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20841之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中’ RNAi劑包含由與AD-20842之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中’ RNAi劑包含由與AD-20843之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 154740.doc -140- 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20844之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20845之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20846之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20847之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中’ RNAi劑包含由與AD-20848之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與ad-20849之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7 ' 8、9或1〇個 154740.doc • 141 - 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20850之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或1〇個 nt (或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-2085 1之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20852之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20861之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20862之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中’ RNAi劑包含由與AD-20863之反義股序 列具有〇、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 154740.doc -142- 201141489 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20864之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20865之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含〇、1、2、3、4、5、6、7、8、9或1〇個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20866之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 在一實施例中，RNAi劑包含由與AD-20867之反義股序 列具有0、1、2或3個錯配之序列組成之反義股，其中反義 股視情況另外包含0、1、2、3、4、5、6、7、8、9或10個 nt(或其任何範圍）。 其他特定具體實施例 在多個實施例中’本發明包含具有有義股及反義股之 RNAi劑’其中反義股包含有〇、1、2或3個nt與本發明揭示 之任何RNAi劑的反義股不同的至少15個連續核普酸。 因此，在多個實施例中： 本發明包含具有有義股及反義股之RNAi劑，其中反義 股包含有0、1、2或3個nt與以下雙鏈體或其經修飾或未經 154740.doc -143- 201141489 修飾之變異體中任何一或多者之反義股不同的至少15個連 續核苷酸：AD-20832、AD-20848、AD-20807、AD-20826 、 AD-20837、AD-20861、AD-20834、AD-20805、 AD-20806 ' AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 、AD-20812、AD-20813、AD-20814、AD-20815、 AD-20816 ' AD-20817 ' AD-20818 ' AD-20819 ' AD-20831; AD-20862; AD-20808; AD-20827; AD-20828; AD-20812; AD-20836 or AD-20822 » In another specific embodiment, the siRNA has AD-20832; AD-20848; AD -20807 , AD-20826 , AD-20837 , AD-20861 , AD-20834 , AD-20806 , AD-20851 , AD-20865 , AD-20811 , AD-20819 , AD-20839 , AD-20835 , AD-20825 AD-20867 , AD-20813 , AD-20823 , AD-20805 , AD-20831 , AD-20862 , AD-20808 , AD-20827 , AD-20828 , AD-20812 , AD-20836 or AD-20822 The sequence of compositions. Multiple Embodiments of RNAi Agents for P-ENaC In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising 0, 1, 2 or 3 nt At least 15 contiguous nucleotides different from the sense strand of AD-20805, the antisense strand comprising 0, 1, 2 or 3 nt differing from its antisense strand by at least 15 contiguous nucleotides. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 0, 1, 2 or 3 nt different from the sense strand of AD-20806 Contiguous nucleotides, the antisense strand contains 0, 154740. Doc -83- 201141489 1, 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising 〇, i, 2 or 3 in a different sense from the sense strand of AD_2〇8〇7 At least 15 contiguous nucleotides comprising at least 5 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand, the sense strand comprising at least one, two or three plus at least one of the AD2〇8〇82 sense strands 15 contiguous nucleotides comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from their antisense strands. In one embodiment, 'the invention comprises a RNAi agent having a sense strand and/or an antisense strand' which comprises at least 15 different from the sense strand of 1, 20 or 3 nt and AD-20809 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand, the 'sense strand comprising at least one of 〇, 1, 2 or 3 nt different from the sense strand of AD-20810 5 contiguous nucleotides comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from their antisense strands. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20811 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different from 0, 1, 2 or 3 nt different from the sense strand of AD-20812 Contiguous nucleotides, the antisense strand contains 0, 154740. Doc • 84· 201141489 1, 2 or 3 nt at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20813 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20814 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In a consistent embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20815. A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, i, 2 or 3 nt different from the sense strand of AD-20816 A contiguous nucleotide comprising at least 5 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, 'the invention comprises a RNAi agent having a sense share and/or an antisense strand' which comprises 0, 1, 2 or 3... at least 15 different from the sense share of AD_2〇817 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand. The stock strand comprises at least 15 consecutive strands of 〇, 2 or 3 different from the AD2〇81k sense strand. Nucleotide, the antisense strand contains 〇, 154740. Doc-85 - 201141489 1, 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least one of 〇, 1, 2 or 3 nt different from the sense share of AD-20819. 5 contiguous nucleotides comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from their antisense strands. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20820 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 0, 1, 2 or 3 nt different from the sense strand of AD-20821 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different 1、, 1, 2 or 3 nt different from the sense strand of AD-20822 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different 1、, 1, 2 or 3 nt different from the sense strand of AD-20823 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising a lexical, 1, 2 or 3 n^AD-2 824 lexical shares different At least 15 contiguous nucleotides, the antisense strand contains 〇, 154740. Doc • 86 - 201141489 1, 2 or 3 nt at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20825 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand, the 'sense strand comprising at least 15 different from the sense strand of AD-20826 comprising 〇, 1, 2 or 3 nt. a contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a sense strand and/or Or an antisense strand of RNAi comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the sense strand of AD-20827, the antisense strand comprising 〇, 1 , 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense share of AD-20828 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different from 0, 1, 2 or 3 nt different from the sense strand of AD-20829 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1 '2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 0, 1, 2 or 3 nt different from the sense strand of AD-20830 a contiguous nucleotide, the antisense strand contains 〇, 154740. Doc • 87· 201141489 1, 2 or 3 nt at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, 'the invention comprises a RNAi agent having a sense strand and/or an antisense strand' which comprises at least 15 different from the sense strand of 1, 20 or 3 nt and AD-20831 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, 'the invention comprises a RNAi agent having a sense share and/or an antisense strand' which comprises at least 15 different i, i, 2 or 3 elbows from the right stock of ad-20832 A contiguous nucleotide comprising at least 15 contiguous nucleotides of hydrazine, 1, 2 or 3 nt different from its antisense strand. In one embodiment, 'the invention comprises a RNAi agent having a sense strand and/or an antisense strand' which comprises at least 15 different from the sense strand of 1, 20 or 3 nt and AD-20833 Contiguous nucleotides comprising at least 15 contiguous nuclei of 〇, 1, 2 or 3 nt different from their antisense strands; acid. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least one, i, 2 or 3 valences different from the correct shares of the gossip-20834 15 contiguous nucleotides comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from their antisense strands. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand. The sense share comprises at least 15 different sense shares of 〇, i, 2 or 3 n^AD-20835. A contiguous nucleotide comprising at least 15 contiguous nucleotides of hydrazine, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20836 Contiguous nucleotides, the antisense strand contains 〇, I54740. Doc •88· 201141489 1, 2 or 3 nt at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand, the sense strand comprising at least one, two or three nt different from the sense strand of AD-2083 7 15 contiguous nucleotides comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from their antisense strands. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20838 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 0, 1, 2 or 3 nt different from the sense strand of AD-20839 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different from 0, 1, 2 or 3 nt different from the sense strand of AD-20840 a contiguous nucleotide comprising 0, 1, 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a sense strand and/or Or an RNAi agent of the antisense strand comprising 0, 1, 2 or 3 nt of at least 15 contiguous nucleotides different from the sense strand of AD-20841, the antisense strand comprising 0, 1 , 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 0, 1, 2 or 3 nt different from the sense strand of AD-20842 Contiguous nucleotides, the antisense strand contains 0, 154740. Doc •89- 201141489 1, 2 or 3 nt at least 15 consecutive nucleotides of acid different from their antisense strands. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different from 0, 1, 2 or 3 nt different from the sense strand of AD-20843 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least 15 different from 0, 1, 2 or 3 nt different from the sense share of AD-20844 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different 1、, 1, 2 or 3 nt from the sense strand of AD-20845 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20846 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 nt different from the sense strand of AD-20847 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 0, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand, the 'sense strand comprising at least 15 different from the sense strand of 1, 20 or 3 nt and AD-20848 a contiguous nucleotide, the antisense strand contains 〇, 154740. Doc •90· 201141489 1, 2 or 3 nt at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, 'the invention comprises a RNAi agent having a sense strand and/or an antisense strand' which comprises at least 15 different from the sense strand of 1, 2 or 3 plus AD2〇849 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment 'the invention comprises a sense strand and/or an antisense strand 2 RNAi agent' which has at least 15 different 1、, 1, 2 or 3 nt different from the sense strand of AD-20850 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a sense strand and/or an antisense strand 2 RNA1 agent. The sense strand comprises at least 15 different from 0, 1, 2 or 3 nt different from the sense strand of AD-20851 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand, the 'sense strand comprising at least 15 different from the sense strand of AD-20852 comprising 〇, 1, 2 or 3 nt. A contiguous nucleotide comprising at least 15 contiguous nucleotides of 1' 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a (10) gossip agent having a sense share and/or an antisense share. The sense share comprises 0, 1, 2 or 3 nt different from the sense share of AD-20861. At least 5 contiguous nucleotides, the antisense strand comprising at least 15 contiguous nucleotides differing from the antisense strand by 〇, 1, 2 or 3 nt. In one embodiment, the invention comprises (10) eighty doses of a stock and/or antisense strand. The stock has a 〇, 1, 2 or 3 nt different from the lexical stock of AD-20862. At least 15 contiguous nucleotides, the antisense strand contains 154,740. Doc •91 · 201141489 0, 1, 2 or 3 nt of at least 15 contiguous nucleotides different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand, the 'sense strand comprising at least 15 different from the sense strand of AD-20863 comprising 〇, 1, 2 or 3 nt A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense strand and/or an antisense strand comprising at least 15 different from the sense strand of ad-20864, 1、, 1, 2 or 3 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least 15 different from the correct strand of ad-20865, 1、, 1, 2 or 3 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least 15 different 〇, 1, 2 or 3 nt different from the AD_2〇866i sense share. A contiguous nucleotide comprising at least 5 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. In one embodiment, the invention comprises a RNAi agent having a sense share and/or an antisense strand comprising at least 15 of 〇, 1, 2 or 3 different from the sense share of ad-20867 A contiguous nucleotide comprising at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from its antisense strand. Multiple Embodiments of RNAi Agents for p-ENaC In one embodiment, the invention relates to compositions comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 cores 154740. Doc -92- 201141489 Glycosylation with AD-20805 (which contains SEQ ID NO.  At least 15 contiguous nucleotides different from the antisense strand of 111-112 and its modified variants) In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, Wherein the antisense strand comprises at least 15 contiguous nucleus different from the antisense strand of AD-20806, which comprises SEQ ID NO. 113-114 and its modified variant, having 〇, 1, 2 or 3 nucleotides Glycosylate. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20807 (including SEQ ID NO.  The antisense strands of 115-116 and its repaired variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20808 (which comprises SEQ ID NO.  The antisense strand of 117-118 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20809 (which comprises At least 15 contiguous nucleotides differ in the antisense strand of SEQ ID NO. 119-120 and its modified variant). In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20810 (including SEQ ID NO.  The antisense strand of 121-122 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc -93· 201141489 Glycosidic acid and AD-20811 (which contains SEQ ID NO.  The antisense strand of 123-124 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20812 (which comprises SEQ ID NO.  The antisense strand of 125-126 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, i, 2 or 3 nucleotides with AD-20813 (which comprises SEQ ID NO.  The antisense strand of 127-128 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20814 (which comprises SEQ ID NO.  The antisense strand of 129-130 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20815 (which comprises SEQ ID NO.  The antisense strand of 131-132 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides and AD_20816 (which comprises SEQ ID NO.  The antisense strand of 133-134 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc -94· 201141489 Glycosidic acid and AD-20817 (which comprises SEQ ID NO.  The antisense strand of 135-136 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20818 (which comprises SEQ ID NO.  At least 15 contiguous nucleotides different from the antisense strand of 137-138 and its modified variants) In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, Wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20819 (which comprises SEQ ID NO.  The antisense strand of 139-140 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20820 (including SEQ ID NO.  The antisense strand of 141-142 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20821 (which comprises SEQ ID NO.  The antisense strand of 143-144 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20822 (which comprises SEQ ID NO.  The antisense strand of 145-146 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc-95-201141489 At least 15 contiguous nucleotides different from the antisense strand of AD-20823, which comprises SEQ ID NO. 147-148 and its modified variants. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, i, 2 or 3 nucleotides with AD-20824 (which comprises SEQ ID NO.  The antisense strands of 149-150 and its modified variants differ by at least 5 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20825 (which comprises SEQ ID NO.  The antisense strands of 151-152 and its modified variants differ by at least 5 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20826 (which comprises SEQ ID NO.  The antisense strand of 153-154 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20827 (which comprises SEq ID NO.  The antisense strand of 155-156 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising an RNA1 agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20828 (including SEq ID NO.  The antisense strand of 157-158 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc 201141489 At least 15 contiguous nucleotides different from the antisense strand of AD-20829, which comprises SEQ ID NO. 159-160 and its modified variants. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20830 (including At least 15 contiguous nucleotides differ in the antisense strand of SEQ ID NO. 161-162 and its modified variant). In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20831 (which comprises The antisense strands of SEQ ID NO. 163-164 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20832 (including SEQ ID NO.  The antisense strand of 165-166 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20833 (which comprises SEQ ID NO.  The antisense strand of 167-168 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20834 (including SEQ ID NO.  The antisense strand of 169-170 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc •97- 201141489 Glycosidic acid with AD-20835 (which contains SEQ ID NO.  The antisense strands of 171-172 and its repaired variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20836 (including At least 15 contiguous nucleotides differ in the antisense strand of SEQ ID NO. 173-174 and its migratory variant). In a consistent embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, }, 2 or 3 nucleotides with AD-20837 (which comprises SEQ ID NO.  The antisense strand of 175-176 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention is directed to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, ! , 2 or 3 nucleotides with AD-20838 (which comprises SEQ ID NO.  The antisense strands of 177-178 and its migratory variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1 '2 or 3 nucleotides with AD-20839 (which comprises SEQ ID NO.  At least 15 consecutive nucleotides of acid differ from the antisense strands of 179-180 and its modified rhythm variants. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20840 (including SEQ ID NO.  The antisense strand of 181-182 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc -98- 201141489 Glycosylation with AD-20841 (which contains SEQ ID NO.  The antisense strand of 183-184 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20842 (which comprises SEQ ID NO.  The antisense strand of 185-186 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD_20843 (which comprises SEQ ID NO.  The antisense strand of 187-188 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20844 (which comprises At least 15 contiguous nucleotides differ in the antisense strand of SEQ ID NO 189-190 and its modified variant). In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20845 (which comprises At least 15 contiguous nucleotides differ in the antisense strand of SEQ ID NO. 191-192 and its modified variant). In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20846 (which comprises SEQ ID NO.  The antisense strand of 193-194 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc -99· 201141489 Glycosidic acid and AD-20847 (which contains SEQ ID NO.  The antisense strand of 195-196 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20848 (which comprises SEq ID NO.  The antisense strand of 197-198 and its modified variant) differs by at least 5 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1 243 nucleotides and AD-20849 (which comprises SEq ID NO.  The antisense strand of 199-200 and its modified variant) differs by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20850 (which comprises SEQ ID NO.  The antisense strands of 201-202 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises guanidine, 1, 2 or 3 nucleosides 1 and gossip-20851 (which comprises At least 15 contiguous nucleotides differing in the antisense strand of SEq ID N〇2〇32〇4 and its modified variant). In a single embodiment, 'the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, or nucleoside l"AD-2〇852 ( It contains seq id NO.  The antisense strands of 205-206 and its modified variants differ by at least 15 contiguous nucleotides. In a single embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises guanidine, 1, 2 or 3 nucleosides 154740. Doc 201141489 Acid with AD-20861 (which contains SEQ ID NO.  The antisense strand of 207-208 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20862 (which comprises SEQ ID NO.  The antisense strand of 209-210 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20863 (which comprises SEQ ID NO· 211-212 and its modified variant) differs from the antisense strand by at least 15 consecutive nucleotides. In one embodiment, the invention relates to a combination of RNAi agents comprising a sense strand and an antisense strand. 'The antisense strand contains 〇, 1, 2 or 3 nucleate and AD-20864 (which contains SEQ ID NO.  At least 15 contiguous nucleotides differ in the antisense strand of 213-214 and its modified variant. In one embodiment, the invention relates to a composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises guanidine, 1, 2 or 3 nucleotides and AD-20865 (which comprises SEQ ID NO.  The antisense strand of 215-216 and its modified variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20866 (which comprises SEQ ID NO.  The antisense strands of 217-218 and its repaired variants differ by at least 15 contiguous nucleotides. In one embodiment, the invention relates to a composition comprising a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises ruthenium, 1, 2 or 3 cores 154740. Doc •101 - 201141489 Glycosidic acid with AD-20867 (which contains SEQ ID NO.  The antisense strand of 219-220 and its modified variant) differs by at least 15 contiguous nucleotides. Multiple Embodiments of RNAi Agents Against p-ENaC In one embodiment, 'the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and ad-20805 ( It contains SEQ ID NO.  The antisense strands of 111 and 112) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises a single nucleotide and AD-20806 (which comprises SEQ ID NO.  In an embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises a single nucleoside The acid is at least 15 contiguous nucleotides different from the antisense strand of ad_20807, which comprises SEQ ID NOs 115 and 116. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and ad_20808 (which comprises SEQ ID NO.  The antisense strands of 117 and 118) differ in at least 15 consecutive nucleotide acids. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20809 (which comprises SEQ ID NO.  The antisense strands of 119 and 120) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc-102-201141489 RNAi agent, wherein the antisense strand comprises one nucleotide and AD-20810 (which comprises SEQ ID NO.  The antisense strands of 121 and 122) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20811 (which comprises SEQ ID NO.  The antisense strands of 123 and 124) differ in at least 15 consecutive nucleotide acids. φ In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20812 (which comprises SEQ ID NO.  The antisense strands of 125 and 126) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20813 (which comprises SEQ ID NO.  The antisense strands of 127 and 128) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20814 (which comprises SEQ ID NO.  The antisense strands of 129 and 130) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20815 (which comprises SEQ ID NO.  The antisense strands of 131 and 132) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a sense strand and an antisense strand. Doc-103-201141489 RNAi agent, wherein the antisense strand contains one nucleotide and AD-20816 (which comprises SEQ ID NO.  The antisense strands of 133 and 134) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20817 (which comprises SEQ ID NO.  13 5 and 13 6) The antisense strand differs by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20818 (which comprises SEQ ID NO.  13 7 and 13 8) The antisense strand differs by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20819 (which comprises SEQ ID NO.  The antisense strands of 139 and 140) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20820 (which comprises SEQ ID NO.  The antisense strands of 141 and 142) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20821 (which comprises SEQ ID NO.  The antisense strands of 143 and 144) differ from at least I5 consecutive nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc • 104· 201141489 RNAi agent, wherein the antisense strand contains 0 nucleotides with AD-20822 (which includes SEQ ID NO.  The antisense strands of 145 and 146) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20823 (which comprises SEQ ID NO.  The antisense strands of 147 and 148) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20824 (which comprises SEQ ID NO.  The antisense strands of 149 and 150) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20825 (which comprises SEQ ID NO.  The antisense strands of 151 and 152) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises a single nucleotide and ad_20826 (which comprises SEQ ID NO.  153 and 15 4) The antisense strands differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises a nucleus Acid and ad-2 〇 827 (which contains SEQ ID NO.  The antisense strands of I55 and 156) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc-105-201141489 RNAi agent, wherein the antisense strand comprises one nucleotide and AD-20828 (which comprises SEQ ID NO.  157 and 15 8) The antisense strand differs from at least 15 consecutive nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20829 (which comprises SEQ ID NO.  At least 15 consecutive cores of different antisense strands of 159 and 160) are acid. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20830 (which comprises SEQ ID NO.  The antisense strands of 161 and 162) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20831 (which comprises SEQ ID NO.  The antisense strands of 163 and 164) differ in at least 15 consecutive nucleotide acids. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20832 (which comprises SEQ ID NO.  The antisense strands of 165 and 166) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20833 (which comprises SEQ ID NO.  The antisense strands of 167 and 168) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc-106-201141489 RNAi agent, wherein the antisense strand comprises one nucleotide and AD-20834 (which comprises SEQ ID NO.  The antisense strands of 169 and 17) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 cores Glycosidic acid with AD-20835 (which comprises SEQ ID NO.  The antisense strands of 171 and 172) differ by at least 15 contiguous nucleotides. φ In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20836 (which comprises SEQ ID NO.  The antisense strands of 173 and 174) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises an antisense strand of 0 nucleotides and AD-20837 comprising SEQ ID NOs 175 and 176 The strands differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20838 (which comprises SEQ ID NO.  The antisense strands of 177 and 178) differ by at least 15 consecutive nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20839 (which comprises SEQ ID NO.  The antisense strands of 179 and 180) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc • 107- 201141489 RNAi agent, wherein the antisense strand contains 0 nucleotides with AD-20840 (which includes SEQ ID NO.  The antisense strands of 181 and 182) differ by at least 15 consecutive nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20841 (which comprises SEQ ID NO.  The antisense strands of 183 and 184) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20842 (which comprises SEQ ID NO.  The antisense strands of 185 and 186) differ by at least 15 consecutive nucleotide acids. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20843 (which comprises SEQ ID NO.  The antisense strands of 187 and 188) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20844 (which comprises SEQ ID NO.  The antisense strands of 189 and 190) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20845 (which comprises SEQ ID NO.  The antisense strands of 191 and 192) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc •108· 201141489 RNAi agent, wherein the antisense strand contains 0 nucleotides with AD-20846 (which includes SEQ ID NO.  At least 15 consecutive nucleotides of acid differ from the antisense strands of 193 and 194). In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20847 (which comprises SEQ ID NO.  The antisense strands of 195 and 196) differ from at least 15 consecutive nucleotides of picric acid. φ In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20848 (which comprises SEQ ID NO.  The antisense strands of 197 and 198) differ from at least 15 consecutive nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20849 (which comprises SEQ ID NO.  199 and 200) antisense strands differ in at least 15 consecutive nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20850 (which comprises SEQ ID NO.  The antisense strands of 201 and 202) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0 nucleotides and AD-20851 (which comprises SEQ ID NO.  The antisense strands of 203 and 204) differ from at least 15 consecutive nucleotides. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc-109-201141489 RNAi agent, wherein the antisense strand contains one nucleotide and AD-20852 (which comprises SEQ ID NO.  The antisense strands of 205 and 206) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20861 (which comprises SEQ ID NO.  The antisense strands of 207 and 208) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20862 (which comprises SEQ ID NO.  The antisense strands of 209 and 210) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and AD-20863 (which comprises SEQ ID NO.  The antisense strands of 211 and 212) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises a single nucleotide and ad_20864 (which comprises SEQ ID NO.  The antisense strands of 213 and 214) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and ad-20865 (which comprises SEQ ID NO.  The antisense strands of 215 and 216) differ by at least 15 contiguous nucleotides'. In one embodiment, the composition comprises 154740 with a positive and antisense stock. Doc-110-201141489 RNAi agent, wherein the antisense strand comprises one nucleotide and AD-20866 (which comprises SEQ ID NO.  The antisense strands of 217 and 218) differ by at least 15 contiguous nucleotides. And in one embodiment, the composition comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises one nucleotide and ad_20867 (which comprises SEQ ID NO.  The antisense strands of 219 and 220) differ by at least 15 contiguous nucleotides. Multiple Embodiments of RNAi Agents for P-ENaC In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1 , 2 or 3 nucleotides with AD-20805 (comprising SEQ ID NO.  At least 15 contiguous nucleotides differing in the antisense sequences of 1 and 2). In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20806 (Includes SEQ ID NO.  At least 15 contiguous nucleotides differ in the antisense sequences of 3 and 4). In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with ad_20807 (including SEQ ID NO.  At least 15 contiguous nucleotides differing in the antisense sequences of 5 and 6). In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with ad-20808 (Includes SEQ ID NO.  At least 15 contiguous nucleotides differ in the antisense sequences of 7 and 8). 154740. Doc 201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD -20809 (includes SEQ ID NO.  The antisense sequences of 9 and 10) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20810 (Includes SEQ ID NO.  The antisense sequences of 11 and 12) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20811 (Includes SEQ ID NO.  The antisense sequences of 13 and 14) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20812 (Includes SEQ ID NO.  The antisense sequences of 15 and 16) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20813 At least 15 contiguous nucleotides differing in the antisense sequence (including SEQ ID NOS 17 and 18). In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20814 At least 15 contiguous nucleotides differing in the antisense sequence (including SEQ ID NOs 19 and 20). 154740. Doc 112-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides With AD-20815 (includes SEQ ID NO.  The antisense sequences of 21 and 22) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20816 (Includes SEQ ID NO.  At least 15 contiguous nucleotides different from the #antisense sequence of 23 and 24) In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein The stock contains 0, 1, 2 or 3 nucleotides with AD-20817 (comprising SEQ ID NO.  The antisense sequences of 25 and 26) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20818 (Includes SEQ ID NO.  27 and 28) • At least 15 contiguous nucleotides differing in the antisense sequence. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20819 (Includes SEQ ID NO.  The antisense sequences of 29 and 30) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20820 (Includes SEQ ID NO.  The antisense sequences of 31 and 32) differ by at least 15 contiguous nucleotides. 154740. Doc-113-201141489 In one embodiment, the composition comprises a modified variant of an RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleosides Acid with AD-20821 (includes SEQ ID NO.  The antisense sequences of 33 and 34) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20822 (Includes SEQ ID NO.  The antisense sequences of 35 and 36) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20823 (Includes SEQ ID NO.  The antisense sequences of 37 and 38) differ by at least 15 contiguous nucleotides. In one embodiment, 'the composition comprises a modified variant of a RNAi agent' wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20824 (Includes SEQ ID NO.  At least 15 consecutive nucleosides differing in the antisense sequences of 39 and 40). In one embodiment, the composition comprises a modified variant of an RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20825 (Includes SEQ ID NO.  The antisense sequences of 41 and 42) differ by at least 15 contiguous nucleotides. In one embodiment, 'the composition comprises a modified variant of a RNAi agent' wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20826 (Includes SEQ ID NO.  The antisense sequences of 43 and 44) differ in at least 15 contiguous nucleotides. 154740. Doc 114 201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides AD-20827 (includes SEQ ID NO.  The antisense sequences of 45 and 46) differ by at least 5 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with aD_2〇828 (Includes SEQ ID NO.  47 and 48) at least 15 contiguous nucleotides differ in the φ antisense sequence. In a consistent embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with ad-20829 (Includes SEQ ID NO.  The antisense sequences of 49 and 50) differ by at least 5 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides and aD_2〇 830 (includes SEQ ID NO.  51 and 52) • At least 15 contiguous nucleotides differing in the antisense sequence. In a consistent embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD_2〇831 (containing at least 15 contiguous nucleotides differing in the antisense sequence of SEQ (1) N〇 53 and 54). In the example, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD_2〇832 At least 15 contiguous nucleotides differing in the antisense sequence (including SEQ ID Ns 55 and 56). 154740. Doc-115-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises guanidine, 1, 2 or 3 nucleosides The acid differs from the antisense sequence of AD-20833 (comprising SEQ ID NO. 57 and 58) by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20834 (Includes SEQ ID NO.  The antisense sequences of 59 and 60) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-2083 5 (includes SEQ ID NO.  The antisense sequences of 61 and 62) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20836 (Includes SEQ ID NO.  The antisense sequences of 63 and 64) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20837 (Includes SEQ ID NO.  The antisense sequences of 65 and 66) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20838 (Includes SEQ ID NO.  The antisense sequences of 67 and 68) differ in at least 15 contiguous nucleotides. 154740. Doc-116-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises guanidine, 1, 2 or 3 nucleosides Acid with AD-20839 (includes SEQ ID NO.  The antisense sequences of 69 and 70) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20840 (Includes SEQ ID NO.  The antisense sequences of 71 and 72) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20841 (Includes SEQ ID NO.  The antisense sequences of 73 and 74) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20842 (Includes SEQ ID NO.  The antisense sequences of 75 and 76) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1 '2 or 3 nucleotides with AD-20843 (Includes SEQ ID NO.  The antisense sequences of 77 and 78) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of the RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20844 (Includes SEQ ID NO.  The antisense sequences of 79 and 80) differ in at least 15 consecutive nucleotides of picric acid. 154740. Doc-117-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleosides The acid differs from the antisense sequence of AD-20845 (comprising SEQ ID NOs 81 and 82) by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20846 (Includes SEQ ID NO.  The antisense sequences of 83 and 84) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20847 (Includes SEQ ID NO.  The antisense sequences of 85 and 86) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20848 (Includes SEQ ID NO.  The antisense sequences of 87 and 88) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20849 (Includes SEQ ID NO.  The antisense sequences of 89 and 90) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of an RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD- At least 15 contiguous nucleotides differing in the antisense sequence of 20850 (including SEQ ID 91 91 and 92). I54740. Doc-118-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleosides Acid with AD-20851 (includes SEQ ID NO.  The antisense sequences of 93 and 94) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20852 (Includes SEQ ID NO.  The antisense sequences of 95 and 96) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20861 (Includes SEQ ID NO.  The antisense sequences of 97 and 98) differ in at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD-20862 (Includes SEQ ID NO.  The antisense sequences of 99 and 100) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD_2〇863 At least 15 contiguous nucleotides differing in the antisense sequence (including SEQ ID N〇1〇1 and 1〇2). In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides with AD_2〇864 At least 5 contiguous nucleotides differing in the antisense sequence (including SEQ ν 〇 1 〇 3 and 1 〇 4). 154740. Doc-119-201141489 In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleosides Acid with AD-20865 (includes SEQ ID NO.  The antisense sequences of 105 and 106) differ by at least 15 contiguous nucleotides. In one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides with AD-20866 (Includes SEQ ID NO.  The antisense sequences of 107 and 108) differ by at least 15 contiguous nucleotides. And in one embodiment, the composition comprises a modified variant of a RNAi agent, wherein the variant comprises a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nucleotides and AD- 20867 (contains SEQ ID NO.  The antisense sequences of 109 and 110) differ by at least 15 contiguous nucleotides. Multiple Examples of RNAi Agents Against p-ENaC In one embodiment, the invention comprises AD-20805 (SEQ ID NOS: 1 and 2, or SEQ ID NOS: 111 and 112). In one embodiment, the invention comprises AD-20806 (SEQ ID NOS: 3 and 4, or SEQ ID NOS: 113 and 114). In one embodiment, the invention comprises AD-20807 (SEQ ID NOS: 5 and 6, or SEQ ID NOS: 115 and 116). In one embodiment, the invention comprises AD-20808 (SEQ ID NOS: 7 and 8, or SEQ ID NOs: 11 7 and 118). In one embodiment, the invention comprises AD-20809 (SEQ ID NOS: 9 and 10, or SEQ ID NOS: 119 and 120). In one embodiment, the invention comprises AD-20810 (SEQ ID NO: 11 and 154740. Doc •120· 201141489 12, or SEQ ID NOS: 121 and 122). In one embodiment, the invention comprises AD-20811 (SEQ ID NOS: 13 and 14, or SEQ ID NOS: 123 and 124). In one embodiment, the invention comprises AD-20812 (SEQ ID NO: 15 and 16, or SEQ ID NO: 125 and 126). In one embodiment, the invention comprises AD-20813 (SEQ ID NOS: 17 and 18, or SEQ ID NOS: 127 and 128). In one embodiment, the invention comprises AD-20814 (SEQ ID NOS: 19 and 20, or SEQ ID NOS: 129 and 1300). In one embodiment, the invention comprises AD_20815 (SEQ ID NOS: 21 and 22, or SEQ ID NOS: 131 and 132). In one embodiment, the invention comprises AD-20816 (SEQ ID NOS: 23 and 24, or SEQ ID NOS: 133 and 134). In one embodiment, the invention comprises ad-2〇817 (SEQ ID NOS: 25 and 26, or SEQ ID NOS: 135 and 136). φ In one embodiment, the invention comprises AD-20818 (SEQ ID NOS: 27 and 28, or SEQ ID NOS: 137 and 138). In one embodiment, the invention encompasses AD 2 〇 819 (SEQ ID NOS: 29 and 30, or SEQ ID NOS: 139 and 140). In one embodiment, the invention comprises AD-20820 (SEQ ID NOS: 31 and 32, or SEQ ID NOS: 141 and 142). In one embodiment, the invention comprises AD-2〇821 (SEQ ID NO..33 and 34, or SEQ ID NQ: 143 and 144). In one embodiment, the invention comprises eight 〇-2〇822 (8 £(^1〇)^0:3 5 and 154740. Doc-121 - 201141489 36, or SEQ ID NO: 145 and 146). In one embodiment, the invention comprises eight to 20823 (8 £(^1〇1^〇: 3 7 and 38, or SEQ ID NOs: 147 and 148). In one embodiment, the invention comprises AD- 20824 (SEQ ID NO: 39 and 40, or SEQ ID NO: 149 and 150). In one embodiment, the invention comprises AD-20825 (SEQ ID NO: 41 and 42, or SEQ ID NO: 151 and 152) In one embodiment, the invention comprises AD-20826 (SEQ ID NOS: 43 and 44, or SEQ ID NOS: 153 and 154). In one embodiment, the invention comprises AD-20827 (SEQ ID NO: 45 and 46, or SEQ ID NOS: 155 and 156). In one embodiment, the invention comprises AD-20828 (SEQ ID NOS: 47 and 48, or SEQ ID NOS: 157 and 158). In the present invention, the invention comprises AD-20829 (SEQ ID NOS: 49 and 50, or SEQ ID NOS: 159 and 160). In one embodiment, the invention comprises AD-20830 (SEQ ID NO: 51 and 52, or SEQ ID NO: 161 and 162). In one embodiment, the invention comprises AD-2083 1 (SEQ ID NOS: 53 and 54, or SEQ ID NOS: 163 and 164). In one embodiment, the invention comprises AD -20832 (SEQ ID NO: 5 5 and 56, or SEQ ID NO: 165 and 166). In one embodiment The invention comprises AD-20833 (SEQ ID NO: 57 and 58, or SEQ ID NO: 167 and 168). In one embodiment, the invention comprises AD-20834 (SEQ ID NO: 59 and 154740. Doc •122· 201141489 60, or SEQ ID NO: 169 and 170). In one embodiment, the invention comprises AD-20835 (SEQ ID NOS: 61 and 62, or SEQ ID NOS: 171 and 172). In one embodiment, the invention comprises AD-20836 (SEQ ID NOS: 63 and 64, or SEQ ID NOS: 173 and 174). In one embodiment, the invention comprises AD-20837 (SEQ ID NOS: 65 and 66, or SEQ ID NO: 175 and 176). • In one embodiment, the invention comprises AD-20838 (SEQ ID NOS: 67 and 68, or SEQ ID NOS: 177 and 178). In one embodiment, the invention comprises AD-20839 (SEQ ID NOS: 69 and 70, or SEQ ID NOS: 179 and 180). In one embodiment, the invention comprises AD-20840 (SEQ NO: 71 and 72, or SEQ ID NO: 181 and 182). In one embodiment, the invention comprises AD-20841 (SEQ ID NOS: 73 and 74, or SEQ ID NO: 183 and 184). In one embodiment, the invention comprises AD-20842 (SEQ ID NOS: 75 and 76, or SEQ ID NOS: 185 and 186). In one embodiment, the invention comprises AD 2 〇 843 (SEQ ID NOS: 77 and 78, or SEQ ID NOS: 187 and 188). In one embodiment, the invention comprises AD2〇844 (SEQ ID NO: 79 and 80, or SEQ ID NO: 189 and 190). In one embodiment, the invention comprises AD-20845 (SEQ ID NOS: 8 1 and 82, or SEQ ID NOS: 191 and 192). In one embodiment, the invention comprises AD-20846 (SEQ ID NO: 83 and 154740. Doc -123- 201141489 84, or SEQ ID NO: 193 and 194). In one embodiment, the invention comprises AD-20847 (SEQ ID NOS: 85 and 86, or SEQ ID NO: 195 and 196). In one embodiment, the invention comprises AD-20848 (SEQ ID NOS: 87 and 88, or SEQ ID NOS: 197 and 198). In one embodiment, the invention comprises AD-20849 (SEQ ID NOS: 89 and 90, or SEQ ID NO: 199 and 200). In one embodiment, the invention comprises AD-2085 0 (SEQ ID NOS: 91 and 92, or SEQ ID NOS: 201 and 202). In one embodiment, the invention comprises AD-20851 (SEQ ID NOS: 93 and 94, or SEQ ID NO: 203 and 204). In one embodiment, the invention comprises AD-20852 (SEQ ID NOS: 95 and 96, or SEQ ID NOS: 205 and 206). In one embodiment, the invention comprises AD-20861 (SEQ ID NOS: 97 and 98, or SEQ ID NOS: 207 and 208). In one embodiment, the invention comprises AD-20862 (SEQ ID NOS: 99 and 100, or SEQ ID NOS: 209 and 210). In one embodiment, the invention comprises AD-20863 (SEQ ID NOS: 101 and 102, or SEQ ID NOS: 211 and 212). In one embodiment, the invention comprises AD-20864 (SEQ ID NOS: 103 and 104, or SEQ ID NOS: 213 and 214). In one embodiment, the invention comprises AD-20865 (SEQ ID NOS: 105 and 106, or SEQ ID NO: 215 and 216). In one embodiment, the invention comprises AD-20866 (SEQ ID NO: 107 154740. Doc -124· 201141489 and 108, or SEQ ID NO: 217 and 218). In one embodiment, the invention comprises AD-20867 (SEQ ID NOS: 109 and 110, or SEQ ID NO: 219 and 220). In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20805. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20806. φ In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20807. In one embodiment, the RNAi agent comprises the exact sequence and length of the antisense strand of AD-20808 Anti-sense stock. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20809. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20810. • In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20811. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20812. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-208 13. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20814. In one embodiment, the RNAi agent comprises the antisense strand of AD-20815 indeed 154740. Doc -125- 201141489 The antisense stocks of the sequence and length. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20816. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20817. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-2081 8 . In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20819. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20820. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20821. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20822. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20823. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20824. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20825. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20826. In one embodiment, the RNAi agent comprises the antisense strand of AD-20827 indeed 154740. Doc -126- 201141489 Cut the sequence and length of the anti-sense stock. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20828. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20829. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20830. φ In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20831. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20832. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20833. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20834. • In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20835. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20836. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20837. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20838. In one embodiment, the RNAi agent comprises the antisense strand of AD-20839 indeed 154740. Doc -127- 201141489 Antisense stocks of sequence and length. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20840. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20841. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20842. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20843. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20844. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20845. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20846. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20847. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20848. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20849. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20850. In one embodiment, the RNAi agent comprises the antisense strand of AD-20851 indeed 154740. Doc -128- 201141489 Antisense stocks of sequence and length. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20852. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20861. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20862. φ In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20863. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20864. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20865. In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20866. # In one embodiment, the RNAi agent comprises an antisense strand of the exact sequence and length of the antisense strand of AD-20867. In various embodiments, the RNAi agent comprising an antisense strand of the exact sequence and length of the antisense strand of the RNAi agent can comprise a modified nucleotide, a 3' end cap, and/or no Other modifications that alter the sequence or length of the RNAi agent. Multiple Embodiments of RNAi Agents Against p-ENaC In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having one, two, or three mismatches with the antisense strand sequence of AD-20805. In one embodiment, the RNAi agent comprises an antisense strand sequence 154740 with AD-20806. Doc -129- 201141489 Columns antisense stocks consisting of ο, 1, 2 or 3 mismatched sequences. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20807. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence of 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20808. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20809. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20810. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20811. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20812. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20813. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20814. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20815. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20816. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20817. In one embodiment, the RNAi agent comprises an antisense strand sequence 154740 with AD-20818. Doc -130- 201141489 Columns antisense strands consisting of 0, 1, 2 or 3 mismatched sequences. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20819. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20820. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20821. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20822. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20823. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20824. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20825. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20826. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20827. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20828. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20829. In a consistent application, the 'RNAi agent contains an antisense strand with 154740. Doc -131 - 201141489 Columns antisense stocks consisting of ο, 1, 2 or 3 mismatched sequences. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20831. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20832. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20833. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20834. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20835. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20836. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20837. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20838. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20839. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having one, two or three mismatches with the antisense strand sequence of AD-20840. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20841. In one embodiment, the RNAi agent comprises an antisense strand sequence 154740 with AD-20842. Doc -132· 201141489 Columns antisense stocks consisting of 0, 1, 2 or 3 mismatched sequences. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20843. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20844. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having one, two or three mismatches with the antisense strand sequence of AD-20845. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20846. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having one, two or three mismatches with the antisense strand sequence of AD-20847. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20848. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20849. In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20850. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of Ad_20851. In one embodiment, the &apos;RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of ad-20852. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having a 〇, 1, 2 or 3 mismatch to the antisense strand sequence of AD-20861. In one embodiment, the RNAi agent comprises an antisense strand sequence 154740 with ad-20862. Doc -133· 201141489 An antisense stock consisting of a sequence of 〇, 1, 2 or 3 mismatches. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20863. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20864. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20865. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20866. In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20867. Multiple Embodiments of RNAi Agents Against P-ENaC In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20805, Wherein the antisense strands additionally include 〇, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof, such as 0-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4 or 2-5 nt, etc.). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20806, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20807, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 154,740. Doc •134- 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20808, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20809, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20810, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20811, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5' 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20812, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20813, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 154,740. Doc -135- 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of ad_20814, wherein the antisense strand additionally comprises 0, 1, 2 as appropriate 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-208 15, wherein the antisense strand optionally comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-208 16, wherein the antisense strand optionally comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20817, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5'6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-208 18, wherein the antisense strand optionally comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20819, wherein the reverse. The stocks include 〇, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 depending on the situation. Doc -136- 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20820, wherein the antisense k optionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20821, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20822, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20823, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20824, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20825, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 1 154 154740. Doc -137· 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20826, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20827, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20828, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20829, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20830, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof) In one embodiment, the RNAi agent comprises 0, 1 from the antisense strand sequence of AD-20831 An antisense stock consisting of 2 or 3 mismatched sequences, wherein the antisense stock optionally includes 〇, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 154,740. Doc •138· 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20832, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20833, wherein the antisense φ strand optionally comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20834, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20835, wherein the antisense Φ strand optionally comprises 〇, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20836, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20837, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 154,740. Doc -139· 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20838, wherein the antisense month additionally comprises 〇, 1 as the case may be , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20839, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8'9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20840, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20841, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having one, two, or three mismatches with the antisense strand sequence of AD-20842, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20843, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 154 154740. Doc -140- 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20844, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20845, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20846, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20847, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20848, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the anti-sense strand sequence of ad-20849, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7 ' 8, 9 or 1 154 154740. Doc • 141 - 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20850, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-2085 1 , wherein the antisense strand optionally comprises 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20852, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20861, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 〇, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20862, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the 'RNAi agent' comprises an antisense strand consisting of a sequence having one, two, or three mismatches with the antisense strand sequence of AD-20863, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 154 154740. Doc -142- 201141489 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20864, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20865, wherein the antisense strand additionally comprises 〇, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 1 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20866, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). In one embodiment, the RNAi agent comprises an antisense strand consisting of a sequence having 0, 1, 2 or 3 mismatches with the antisense strand sequence of AD-20867, wherein the antisense strand additionally comprises 0, 1, as appropriate 2, 3, 4, 5, 6, 7, 8, 9 or 10 nt (or any range thereof). Other Specific Embodiments In various embodiments, 'the invention comprises a RNAi agent having a sense strand and an antisense strand' wherein the antisense strand comprises 〇, 1, 2 or 3 nt and any of the RNAi agents disclosed herein The antisense strand differs by at least 15 consecutive nucleotides. Thus, in various embodiments: the invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nt and the following duplex or modified or not thereof By 154740. Doc -143- 201141489 At least 15 contiguous nucleotides of different antisense strands of any one or more of the modified variants: AD-20832, AD-20848, AD-20807, AD-20826, AD-20837, AD -20861, AD-20834, AD-20805, AD-20806 'AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 , AD-20812 , AD-20813 , AD-20814 , AD-20815 , AD-20816 ' AD-20817 ' AD-20818 ' AD-20819 ' AD-

20820 &gt; AD-20821、AD-20822、AD-20823、AD-20824、 AD-20825 ' AD-20827 ' AD-20828 ' AD-20829 ' AD- 20830 ' AD-2083 1、AD-20833、AD-20835、AD-20836、 AD-20838 ' AD-20839 &gt; AD-20840 ' AD-20841 ' AD-20842 ' AD-20843、AD-20844、AD-20845 ' AD-20846、 AD-20847 ' AD-20849 ' AD-20850 ' AD-20851 ' AD-20852 ' AD-20862、AD-20863 ' AD-20864、AD-20865、 AD-20866、AD-20867或其經修飾或未經修飾之變異體。 其他特定具體實施例 在多個實施例中，本發明包含具有第一股及第二股之 RNAi劑，其中第一股序列包含有0、1、2或3個nt與本文揭 示之任何RNAi劑之第一股序列不同的至少15個連續核苷 酸且第二股序列包含有0、1、2或3個核苷酸與第二股序列 不同的至少15個連續核苷酸。 因此，在多個實施例中： 本發明包含具有有義股及反義股之RNAi劑，其中第一 股之序列包含有〇、1、2或3個nt與以下雙鏈體或其經修飾 或未經修飾之變異體中任何一或多者之第一股序列不同的 154740.doc •144· 201141489 至少1 5個連續核苷酸，且第二股之序列包含有ο、1、2或3 個核苷酸與其第二股序列不同的至少15個連續核苷酸： AD-20832 ' AD-20848 ' AD-20807 ' AD-20826 ' AD- 20837 ' AD-20861 ' AD-20834 ' AD-20805 ' AD-20806 ' AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 ' AD- 20812 ' AD-20813 ' AD-20814 ' AD-20815 ' AD-20816 ' AD-20817 &gt; AD-20818 ' AD-20819 ' AD-20820 ' AD-20820 &gt; AD-20821, AD-20822, AD-20823, AD-20824, AD-20825 'AD-20827 'AD-20828 'AD-20829 'AD-20830 ' AD-2083 1, AD-20833, AD- 20835, AD-20836, AD-20838 'AD-20839 &gt; AD-20840 'AD-20841 'AD-20842 'AD-20843, AD-20844, AD-20845 'AD-20846, AD-20847 ' AD-20849 ' AD-20850 ' AD-20851 ' AD-20852 ' AD-20862, AD-20863 ' AD-20864, AD-20865, AD-20866, AD-20867 or modified or unmodified variants thereof. Other Specific Embodiments In various embodiments, the invention comprises a RNAi agent having a first strand and a second strand, wherein the first strand sequence comprises 0, 1, 2 or 3 nts and any of the RNAi agents disclosed herein The first sequence differs by at least 15 contiguous nucleotides and the second strand comprises at least 15 contiguous nucleotides having 0, 1, 2 or 3 nucleotides different from the second strand sequence. Thus, in various embodiments: The invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the sequence of the first strand comprises 〇, 1, 2 or 3 nt and the following duplex or modified thereof Or the first sequence of any one or more of the unmodified variants is different 154740.doc • 144· 201141489 at least 1 5 contiguous nucleotides, and the sequence of the second strand contains ο, 1, 2 or 3 nucleotides differing from its second strand by at least 15 contiguous nucleotides: AD-20832 ' AD-20848 ' AD-20807 ' AD-20826 ' AD- 20837 ' AD-20861 ' AD-20834 ' AD- 20805 ' AD-20806 ' AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 ' AD-20812 ' AD-20813 ' AD-20814 ' AD-20815 ' AD-20816 ' AD-20817 &gt; AD-20818 ' AD-20819 ' AD-20820 ' AD-

20821 、AD-20822、AD-20823、AD-20824、AD-20825、 AD-20827 ' AD-20828 ' AD-20829 ' AD-20830 ' AD- 20831 ' AD-20833 ' AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD-20840 ' AD-20841 ' AD-20842 ' AD- 20843 ' AD-20844 ' AD-20845 &gt; AD-20846、AD-20847、 AD-20849 ' AD-20850 ' AD-20851 ' AD-20852 ' AD- 20862 ' AD-20863、AD-20864、AD-20865 ' AD-20866 &gt; AD-20867或其經修飾或未經修飾之變異體。 額外特定實施例 在多個實施例中，本發明包含具有有義股及反義股之 RNAi劑’其中反義股包含本文揭示之任何RNAi劑的反義 股或由本文揭示之任何RNAi劑的反義股組成》 因此，提供以下作為多個實施例之實例。 本發明包含具有有義股及反義股之RNAi劑，其中反義 股包含以下反義股或由以下反義股組成：AD-20832、AD-20848 ' AD-20807、AD-20826、AD-20837 ' AD-20861 ' AD-20834 、 AD-20805 、 AD-20806 、 AD-20808 、 AD- 154740.doc •145· 201141489 20809、AD-20810、AD-20811、AD-20812、AD-20813、 AD-20814 ' AD-20815 ' AD-20816 ' AD-20817 ' AD- 20818 ' AD-20819 ' AD-20820、AD-20821、AD-20822、 AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD- 20828 ' AD-20829 ' AD-20830、AD-2083 1、AD-20833、 AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD- 20840 ' AD-20841 ' AD-20842 ' AD-20843 ' AD-20844 &gt; AD-20845 ' AD-20846 ' AD-20847 ' AD-20849 ' AD- 20850 ' AD-20851、AD-20852、AD-20862、AD-20863、 AD-20864、AD-20865、AD-20866、AD-20867 或其經修飾 或未經修飾之變異體。 在多個實施例中，本發明包含具有有義股及反義股之 RNAi劑，其中反義股包含有0、1、2或3個nt與本文揭示之 任何RNAi劑或其經修飾或未經修飾之變異體之反義股不 同的至少1 5個連續核苷酸，其中反義股視情況另外包含 0、1、2、3、4、5、6、7、8、9或 10個或 10個以上 nt(或其 任何範圍，例如0 -1、1 - 2、1 _3、1 - 4個nt等）。 因此，在多個實施例中，本發明包含具有有義股及反義 股之RNAi劑，其中反義股包含有0、1、2或3個nt與以下之 反義股不同的至少15個連續核苷酸：AD-20832、AD-20848 、 AD-20807、AD-20826、AD-20837、AD-20861、 AD-20834 ' AD-20805 ' AD-20806 ' AD-20808 &gt; AD-20809 ' AD-20810、AD-2081 1、AD-20812、AD-20813 &gt; AD-20814 、 AD-20815 、 AD-20816 、 AD-20817 、AD- 154740.doc -146- 201141489 20818、AD-20819、AD-20820 ' AD-20821 'AD-20822、 AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD- 20828 ' AD-20829、AD-20830 ' AD-20831、AD-20833、 AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD- 20840 ' AD-20841 ' AD-20842 ' AD-20843、AD-20844 ' AD-20845 ' AD-20846 ' AD-20847 ' AD-20849 ' AD- 20850 ' AD-20851、AD-20852、AD-20862、AD-20863、 AD-20864、AD-20865 ' AD-20866、AD-20867或其經修飾 或未經修飾之變異體，其中反義股視情況另外包含0、1、 2、3、4、5、6、7' 8、9或10或10個以上nt(或其任何範 圍，例如0-1、1-2、1-3、1-4 個 nt等）。 在多個實施例中，本發明包含具有第一及第二股之 RNAi劑，其中第一股之序列包含本文揭示之任何RNAi劑 或其經修飾或未經修飾之變異體的第一股序列或由本文揭 示之任何RNAi劑或其經修飾或未經修飾之變異體的第一 股序列組成，且第二股之序列包含其第二股序列或由其第 二股序列組成。 因此，在多個實施例中，本發明包含具有第一及第二股 之RNAi劑，其中第一股之序列包含以下之第一股序列或 由以下之第一股序列組成，且第二股之序列包含以下之第 二股序列或由以下之第二股序列組成：AD-20832、AD-20848 、 AD-20807、AD-20826 ' AD-20837、AD-20861、 AD-20834 ' AD-20805 ' AD-20806 &gt; AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 ' AD-20812 ' AD-20813 ' 154740.doc • 147- 201141489 AD-20814 ' AD-20815 ' AD-20816 ' AD-20817 ' AD- 20818 ' AD-20819、AD-20820、AD-20821 ' AD-20822 ' AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD-20828 ' AD-20829 ' AD-20830、AD-20831、AD-20833、 AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 &gt; AD-20840 ' AD-20841、AD-20842、AD-20843、AD-20844 ' AD-20845 ' AD-20846 ' AD-20847 ' AD-20849 ' AD-20850 ' AD-20851、AD-20852 &gt; AD-20862 &gt; AD-20863、 AD-20864、AD-20865、AD-20866、AD-20867 ° 在一實施例中，本發明包含本文所列之任何一或多種 RNAi 劑。 針對p-ENaC之RNAi劑的重疊組 在多個實施例中，本發明係關於具有重疊序列之針對β-ENaC之RNAi劑的群。因此，本發明涵蓋RNAi劑之群，其 中群中之各RNAi劑與同一群中之各其他RNAi劑重疊至少 5、6、7、8、9、10、11、12、13、14、15、16、17、 18、19或19個以上核苷酸。特定言之，在一實施例中，重 疊為至少12個nt。 本文所列之一些RNAi劑的序列彼此重疊。表2呈現重疊 RNAi劑之此等群中之一些的彙編，其中群之各成員與同 一群中之各其他成員重疊至少12個nt。呈現有義股及反義 股之12-nt重疊部分。 因此，舉例而言，如表2所示，RNAi劑AD-20807及AD-20832 之序 列重疊 ，其 中有義 股中之 重疊包 含序列 154740.doc -148- 201141489 UGAAGAAGUACC(SEQ ID NO: 223);此等 RNAi劑的反義 股序列亦重疊，其中重疊包含序列GGUACUUCUUCA(SEQ ID NO: 224)。RNAi劑 AD-20807、AD-20862及 AD-20832均 在有義股中重疊，其中重疊包含序列 GAAGAAGUACCU(SEQ ID NO. 225);此等 RNAi劑之反義 股亦重疊，其中重疊包含序列AGGUACUUCUUC(SEQ ID NO: 226)。因此’表2所呈現之重疊RNAi劑之此等及其他 多個組共有常見技術特徵，例如有義股及反義股中之重 疊。 下表2中提供針對β-ENaC之重疊RNAi劑的特定組。 本發明因此涵蓋包含常見技術特徵之RNAi劑的任何群 或子群’其中常見技術特徵為有義股或反義股中之序列重 疊（例如至少12個nt)。 因此： 本發明涵蓋具有反義股及/或有義股之RNAi劑：該反義 股包含有〇、1、2或3個nt與任一以下群中之反義股不同的 至少15個連續核苷酸’該有義股包含有〇、1、2或3個…與 任一以下群中之有義股不同的至少1 5個連續核苷酸：AD- 20807及八0-20832(或表2中呈現之任何其他群）。 本發明涵蓋具有第一股及第二股之RNAi劑，其中第一 股包含有〇、1、2或3個nt與任一以下群中之第一股不同的 至少15個連續核苷酸’及/或第二股包含有〇、1、2或3個nt 與任一以下群中之第二股不同的至少15個連續核苷酸： AD-20807及AD-2083 2(或表2中表示之任何其他群）。 154740.doc -149- 201141489 一股及第二股之RNAi劑，其中第一20821, AD-20822, AD-20823, AD-20824, AD-20825, AD-20827 'AD-20828 ' AD-20829 ' AD-20830 ' AD-20831 ' AD-20833 ' AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD-20840 ' AD-20841 ' AD-20842 ' AD-20843 ' AD-20844 ' AD-20845 &gt; AD-20846, AD-20847, AD-20849 ' AD-20850 ' AD -20851 'AD-20852 ' AD-20862 ' AD-20863, AD-20864, AD-20865 ' AD-20866 &gt; AD-20867 or its modified or unmodified variants. Additional Specific Embodiments In various embodiments, the invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises an antisense strand of any of the RNAi agents disclosed herein or by any of the RNAi agents disclosed herein Antisense Unit Compositions Accordingly, the following examples are provided as a plurality of embodiments. The present invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises the following antisense strand or consists of the following antisense strands: AD-20832, AD-20848 'AD-20807, AD-20826, AD- 20837 'AD-20861 ' AD-20834 , AD-20805 , AD-20806 , AD-20808 , AD- 154740.doc •145· 201141489 20809, AD-20810, AD-20811, AD-20812, AD-20813, AD -20814 ' AD-20815 ' AD-20816 ' AD-20817 ' AD- 20818 ' AD-20819 ' AD-20820, AD-20821, AD-20822, AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD- 20828 ' AD-20829 ' AD-20830, AD-2083 1, AD-20833, AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD- 20840 ' AD-20841 ' AD-20842 ' AD-20843 ' AD-20844 &gt; AD-20845 ' AD-20846 ' AD-20847 ' AD-20849 ' AD- 20850 ' AD-20851, AD-20852, AD-20862, AD-20863, AD-20864, AD -20865, AD-20866, AD-20867 or modified or unmodified variants thereof. In various embodiments, the invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises 0, 1, 2 or 3 nt with any of the RNAi agents disclosed herein or modified or not thereof The antisense strand of the modified variant differs by at least 15 contiguous nucleotides, wherein the antisense strand optionally comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 Or more than 10 nt (or any range thereof, such as 0 -1, 1 - 2, 1 _3, 1-4 nt, etc.). Accordingly, in various embodiments, the invention comprises a RNAi agent having a sense strand and an antisense strand, wherein the antisense strand comprises at least 15 different from 0, 1, 2 or 3 nt different from the antisense strand below Continuum nucleotides: AD-20832, AD-20848, AD-20807, AD-20826, AD-20837, AD-20861, AD-20834 'AD-20805 'AD-20806 'AD-20808 &gt; AD-20809 ' AD-20810, AD-2081 1, AD-20812, AD-20813 &gt; AD-20814, AD-20815, AD-20816, AD-20817, AD-154740.doc -146- 201141489 20818, AD-20819, AD -20820 ' AD-20821 'AD-20822, AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD-20828 ' AD-20829, AD-20830 ' AD-20831, AD-20833, AD-20835 ' AD-20836 ' AD-20838 ' AD-20839 ' AD- 20840 ' AD-20841 ' AD-20842 ' AD-20843 , AD-20844 ' AD-20845 ' AD-20846 ' AD-20847 ' AD-20849 ' AD - 20850 'AD-20851, AD-20852, AD-20862, AD-20863, AD-20864, AD-20865 'AD-20866, AD-20867 or modified or unmodified variants thereof, of which antisense stock Included as an additional 0, 1, 2, 3, 4, 5, 6, 7' 8, 9 or 10 or more nt (or any of them) Encircles, for example, 0-1, 1-2, 1-3, 1-4 nt, etc.). In various embodiments, the invention comprises a RNAi agent having a first and a second strand, wherein the first strand sequence comprises the first strand of any of the RNAi agents disclosed herein, or a modified or unmodified variant thereof Or consisting of the first strand of any of the RNAi agents disclosed herein, or modified or unmodified variants thereof, and the second strand sequence comprises or consists of its second strand sequence. Thus, in various embodiments, the invention comprises a RNAi agent having a first and a second strand, wherein the sequence of the first strand comprises or consists of the first strand sequence below, and the second strand The sequence consists of the following second strand sequence or consists of the following second strand sequence: AD-20832, AD-20848, AD-20807, AD-20826 'AD-20837, AD-20861, AD-20834 'AD-20805 ' AD-20806 &gt; AD-20808 ' AD-20809 ' AD-20810 ' AD-20811 ' AD-20812 ' AD-20813 ' 154740.doc • 147- 201141489 AD-20814 ' AD-20815 ' AD-20816 ' AD -20817 ' AD- 20818 ' AD-20819, AD-20820, AD-20821 ' AD-20822 ' AD-20823 ' AD-20824 ' AD-20825 ' AD-20827 ' AD-20828 ' AD-20829 ' AD-20830 , AD-20831, AD-20833, AD-20835 'AD-20836 'AD-20838 'AD-20839 &gt; AD-20840 'AD-20841, AD-20842, AD-20843, AD-20844 'AD-20845' AD-20846 ' AD-20847 ' AD-20849 ' AD-20850 ' AD-20851, AD-20852 &gt; AD-20862 &gt; AD-20863, AD-20864, AD-20865, AD-20866, AD-20867 ° In one embodiment, the invention encompasses any one or more of the RNAi listed herein Agent. Overlapping Sets of RNAi Agents Against p-ENaC In various embodiments, the present invention relates to populations of RNAi agents against β-ENaC having overlapping sequences. Accordingly, the invention encompasses a population of RNAi agents, wherein each RNAi agent in the population overlaps with each other RNAi agent in the same population by at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more nucleotides. In particular, in one embodiment, the overlap is at least 12 nt. The sequences of some of the RNAi agents listed herein overlap with each other. Table 2 presents a compilation of some of these populations of overlapping RNAi agents, wherein each member of the population overlaps with each other member of the same population by at least 12 nt. Presents a 12-nt overlap of the stock and antisense stocks. Thus, for example, as shown in Table 2, the sequences of the RNAi agents AD-20807 and AD-20832 overlap, wherein the overlap in the sense strand comprises the sequence 154740.doc-148-201141489 UGAAGAAGUACC (SEQ ID NO: 223); The antisense strand sequences of these RNAi agents also overlap, wherein the overlap comprises the sequence GGACAPUCUUCIA (SEQ ID NO: 224). The RNAi agents AD-20807, AD-20862 and AD-20832 all overlap in the sense strand, wherein the overlap comprises the sequence GAAGAAGUACCU (SEQ ID NO. 225); the antisense strands of these RNAi agents also overlap, wherein the overlap comprises the sequence AGGUACUUCUUC (SEQ ID NO: 226). Thus, these and other groups of overlapping RNAi agents presented in Table 2 share common technical features, such as overlaps in the sense and antisense strands. Specific groups of overlapping RNAi agents for β-ENaC are provided in Table 2 below. The invention thus encompasses any population or subgroup of RNAi agents comprising common technical features&apos; wherein a common technical feature is the overlapping of sequences in a sense strand or an antisense strand (e.g., at least 12 nt). Thus: the invention encompasses an RNAi agent having an antisense strand and/or a sense strand comprising: at least 15 consecutive strands of 〇, 1, 2 or 3 nt different from the antisense strands of any of the following groups Nucleotide 'The sensible strand contains at least 1 5 contiguous nucleotides different from the sense strands in any of the following groups: 1, 20-80 and 8-20-20 (or Any other group presented in Table 2). The invention encompasses a first and second strand of RNAi agent, wherein the first strand comprises at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the first strand of any of the following populations' And/or the second strand comprises at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nt different from the second strand of any of the following groups: AD-20807 and AD-2083 2 (or Table 2) Any other group indicated). 154740.doc -149- 201141489 One and second RNAi agents, the first of which

本發明涵蓋具有第 股包含任一以下群令 一股序列組成，及/启 序列或由任一以下我 及第二股可視情況共價連接、經環或連接子連接、或連 續），且其中第一及/或第二股包含與任一以下群有〇、12 或3個nt或bp錯配之序列、基本上由或由與任一以下群有 0、1、2或3個nt或bp錯配之序列組成：ad_2〇8〇7&amp;ad_ 20832(或表2中表示之任何其他群），視情況另外包含〇1〇 個nt或bp。 本發明類似地涵蓋多個實施例’其涵蓋表2中呈現之重 疊RNAi劑之群。 其他定義 如本文及申請專利範圍中使用之冠詞「一」係指一個或 一個以上（至少一個）冠詞的語法目標。 術語「RNAi劑」及其類似術語均係指（但不限於）一或多 種本發明之RNAi劑。 本文揭示之針對β-ENaC之RNAi劑的特定實例雙鍵體之 命名有時在數字後具有字尾「b」。此指示批號。因此，字 尾「bl」指示「批次1」。因此’命名為例如「AD-20807-bl」之RNAi雙鏈體特定來自批次1，且具有與命名為 「AD-20807」之任何RNAi劑相同之序列。 154740.doc • 150- 201141489 明：η，否則本文所用之科技術語具有熟悉本發 明所屬領域之專家一般理解相同之含義。 除非另外指出，否則可如孰缋祛a 口 h 熟練技術人員所瞭解使用本身 已知之方式進行且已進行本文未特定詳細描述之所有方 法、步驟、技術及操作1如再次參考標準手冊及本文提 及之一般背景技術及其中引用之其他參考文獻。The invention encompasses having a singular strand comprising any one of the following groupings, a sequence of sequences, and/or a sequence or by any of the following I and II shares covalently linked, via a ring or a linker, or contiguous), and wherein The first and/or second strands comprise a sequence that has a 〇, 12 or 3 nt or bp mismatch to any of the following populations, consists essentially of or consists of 0, 1, 2 or 3 nt with or The sequence composition of the bp mismatch is: ad_2〇8〇7&amp;ad_ 20832 (or any other group represented in Table 2), optionally including 〇1 nt or bp. The invention similarly encompasses multiple embodiments' which encompasses the population of overlapping RNAi agents presented in Table 2. Other Definitions The articles "a" as used herein and in the context of the claims are intended to mean the grammatical target of one or more (at least one). The term "RNAi agent" and the like are used to mean, but are not limited to, one or more of the RNAi agents of the invention. The naming of the specific example double bond of the RNAi agent disclosed herein for β-ENaC sometimes has the suffix "b" after the number. This indicates the lot number. Therefore, the word "bl" indicates "batch 1". Thus, an RNAi duplex designated as "AD-20807-bl", for example, is specifically from Lot 1 and has the same sequence as any RNAi agent designated "AD-20807". 154740.doc • 150- 201141489 明: η, otherwise the technical terms used herein have the same meaning as commonly understood by experts familiar with the art to which the invention pertains. Unless otherwise indicated, all methods, procedures, techniques, and operations that have been described in a manner known per se and that have not been specifically described herein are to be understood by those skilled in the art. And the general background art and other references cited therein.

本發明之申請專利範圍為非限制性的且提供於下文中。 儘管本文已詳細揭示料實施例及中請專利範圍，但此 已出於僅說明之目的藉由實例之方式進行，且不欲限制隨 时請專利範圍之㈣，或任何相應將來中請案之申請專 利觀圍的主日之嘴。詳言之，本發明者預期可對本發明 作出多個取代、改變及修改而不棒離中請專利範圍所界定 的本發明之㈣及料。咸信核酸起始物質、所關注純系 或庫類型之選擇為具有本文所述實施例之知識的一般技術 者的常規問題。認為其他態樣、優勢及修改在隨附申請專 圍的範脅内。在後申請之相應申請案的申請專利範圍 1已脅之改寫可％又各國之專利法限制’且不應解釋為放棄 申請專利範圍之主旨。 -般技術人員可作出所述針對p_ENaC2RNA_的多種 2他調配及明顯變體。非限制性針對β-ENaC之RNAi劑的 實例&amp;述於f t實例中’其不限制如中請專利範圍中所述 的本發明之範疇。 實例 實例1 154740.doc -151 - 201141489 生物資訊及P-ENaC RNAi劑（siRNA)序列 進行β-ENaC寡核苷酸設計以識別靶向編碼β-ENaC基因 之mRNA的siRNA [來自人類之「鈉通道，非電壓閘控1β」 (NCBI人類符號SCNN1B)及來自石蟹獼猴及大鼠（褐家鼠 (Rattus norvegicus))之直系同源序列]。設計方法使用來自 人類之 SCNNB1 轉錄物 NM_000336.2(NCBI Geneld 6338)、 來自大鼠之NM_012648.1(NCBI Geneld 24767)及全長石 蟹獼猴序列（本文所述）。 所有siRNA雙鏈體經設計以與所有三種SCNNB 1轉錄物 100°/。一致。所有序列均來自轉錄物NM_000336。 未經修飾及經修飾序列列於表1中。未經修飾序列包括 作為SEQ ID NO: 111至220列出之有義序列及反義序列。 亦提供與SEQ ID NO: 222中之人類β-ENaC轉錄物比較的第 一殘基之相對位置。 如下文所述，表1亦提供此等序列之經修飾變異體實例 (SEQ ID NO: 1至110)。自表1之各行，「S」表示有義股， 「AS」表示反義股，且「Pos’n」表示第一核苷酸之位 置。如小寫字母（例如「c」及「u」）表示之經修飾核苷酸 描述於下表1八中》 在表1中之序列中，經修飾及未經修飾序列可視情況在 3'端包含序列「dTsdT」。因此’例如’ AD-20805可視情況 具有有義股中之經修飾序列cAGuGAcuAcAAcAcGAccdTsdT (SEQ ID NO: 429)及反義股中之GGUCGUGUUGuAGUcACUGdTsdT (SEQ ID NO: 430)。如下表1A中所述，dT為2··去氧-胸苷· 154740.doc •152· 201141489 5，_填酸醋真sdT為2’-去氧胸苷5’-硫代磷酸酯。 表l.p-ENaC序列The patent application scope of the present invention is non-limiting and is provided below. Although the scope of the invention and the scope of the patent application have been disclosed in detail herein, it has been described by way of example only, and is not intended to limit the scope of the patent (4), or any corresponding future case. The mouth of the main day for applying for a patent. In particular, the inventors contemplate that various substitutions, changes and modifications may be made to the invention without departing from the scope of the invention as defined by the scope of the invention. Selection of a salty nucleic acid starting material, a pure line of interest, or a type of library is a matter of general skill to those of ordinary skill in the art having the embodiments described herein. Other aspects, advantages, and modifications are considered to be within the scope of the accompanying application. In the subsequent application, the scope of application for a patent application 1 has been threatened to be rewritten by % and the patent law of each country' and should not be construed as a waiver of the scope of the patent application. The skilled person can make the various 2 hists and distinct variants for p_ENaC2RNA_. Non-limiting examples of RNAi agents for β-ENaC are described in the 'f example' and are not limited to the scope of the invention as described in the scope of the patent application. EXAMPLES Example 1 154740.doc -151 - 201141489 Bioinformatics and P-ENaC RNAi Agent (siRNA) Sequences The β-ENaC oligonucleotide was designed to recognize siRNA targeting mRNA encoding the β-ENaC gene [sodium from humans Channel, non-voltage gated 1β” (NCBI human symbol SCNN1B) and orthologous sequence from stone crab macaque and rat (Rattus norvegicus). The design method used the human SCNNB1 transcript NM_000336.2 (NCBI Geneld 6338), rat NM_012648.1 (NCBI Geneld 24767) and full length stone crab macaque sequence (described herein). All siRNA duplexes were designed to encode 100°/ with all three SCNNB 1 transcripts. Consistent. All sequences were from the transcript NM_000336. Unmodified and modified sequences are listed in Table 1. The unmodified sequence includes the sense sequence and the antisense sequence set forth as SEQ ID NOS: 111 to 220. The relative position of the first residue compared to the human β-ENaC transcript of SEQ ID NO: 222 is also provided. Table 1 also provides examples of modified variants of these sequences (SEQ ID NOS: 1 to 110), as described below. From the rows of Table 1, "S" indicates the right stock, "AS" indicates the antisense stock, and "Pos'n" indicates the position of the first nucleotide. Modified nucleotides such as lowercase letters (such as "c" and "u") are described in Table 1 below. In the sequence in Table 1, the modified and unmodified sequences are optionally included at the 3' end. The sequence "dTsdT". Thus, for example, 'AD-20805' may optionally have a modified sequence cAGuGAcuAcAAcAcGAccdTsdT (SEQ ID NO: 429) in the sense strand and GGUCGUGUUGuAGUcACUGdTsdT (SEQ ID NO: 430) in the antisense strand. As described in Table 1A below, dT is 2··deoxy-thymidine·154740.doc •152·201141489 5,_The acid vinegar true sdT is 2'-deoxythymidine 5'-phosphorothioate. Table 1. p-ENaC sequence

雙鏈體ID SEQ ID 經修飾序列 SEQ ID 未經修飾序列 Pos'n AD-20805 S 1 c AGu G Acu Ac AAc AcG Acc 111 CAGUGACUACAACACGACC 1298 AS 2 GGUCGUGUUGuAGUcACUG 112 GGUCGUGUUGUAGUCACUG 1298 AD-20806 S 3 AuGAcAGAGAAGGcAcuuc 113 AUGACAGAGAAGGCACUUC 1011 AS 4 GAAGUGCCUUCUCUGUcAU 114 GAAGUGCCUUCUCUGUCAU 1011 AD-20807 S 5 GuGAAGAAGuAccuGcuGA 115 GUGAAGAAGUACCUGCUGA 183 AS 6 UcAGcAGGuACUUCUUcAC 116 UCAGCAGGUACUUCUUCAC 183 AD-20808 S 7 GuGAcuAcAAcAcGAccuA 117 GUGACUACAACACGACCUA 1300 AS 8 uAGGUCGUGUUGuAGUcAC 118 UAGGUCGUGUUGUAGUCAC 1300 AD-20809 S 9 GGuGGAGGcccAcAccAAc 119 GGUGGAGGCCCACACCAAC 1919 AS 10 GUUGGUGUGGGCCUCcACC 120 GUUGGUGUGGGCCUCCACC 1919 AD-20810 S 11 uGGuGGAGGcccAcAccAA 121 UGGUGGAGGCCCACACCAA 1918 AS 12 UUGGUGUGGGCCUCcACcA 122 UUGGUGUGGGCCUCCACCA 1918 AD-20811 S 13 uuccAAGAccAcAuGAucc 123 UUCCAAGACCACAUGAUCC 1347 AS 14 GGAUcAUGUGGUCUUGGAA 124 GGAUCAUGUGGUCUUGGAA 1347 AD-20812 S 15 AGcuGGGAGGucAGcGucu 125 AGCUGGGAGGUCAGCGUCU 402 AS 16 AGACGCUGACCUCCcAGCU 126 AGACGCUGACCUCCCAGCU 402 AD-20813 S 17 GGGAGAAAuAcuGcAAcAA 127 GGGAGAAAUACUGCAACAA 1408 AS 18 UUGUUGcAGuAUUUCUCCC 128 UUGUUGCAGUAUUUCUCCC 1408 AD-20814 S 19 ccAGuuuGGcuucuGGAuG 129 CCAGUUUGGCUUCUGGAUG 1748 AS 20 cAUCcAGAAGCcAAACUGG 130 CAUCCAGAAGCCAAACUGG 1748 AD-20815 S 21 AGuGAcuAcAAcAcGAccu 131 AGUGACUACAACACGACCU 1299 AS 22 AGGUCGUGUUGuAGUcACU 132 AGGUCGUGUUGUAGUCACU 1299 AD-20816 S 23 AAuAucAcccuGAGcAGGA 133 AAUAUCACCCUGAGCAGGA 1626 AS 24 UCCUGCUcAGGGUGAuAUU 134 UCCUGCUCAGGGUGAUAUU 1626 AD-20817 S 25 ccuGcAGGccAccAAcAuc 135 CCUGCAGGCCACCAACAUC 836 AS 26 GAUGUUGGUGGCCUGcAGG 136 GAUGUUGGUGGCCUGCAGG 836 AD-20818 s 27 AucAcccuGAGcAGGAAGG 137 AUCACCCUGAGCAGGAAGG 1629 AS 28 CCUUCCUGCUcAGGGUGAU 138 CCUUCCUGCUCAGGGUGAU 1629 AD-20819 s 29 GcuGGGAGGucAGcGucuc 139 GCUGGGAGGUCAGCGUCUC 403 AS 30 GAGACGCUGACCUCCcAGC 140 GAGACGCUGACCUCCCAGC 403 AD-20820 s 31 GAGcuGGGAGGucAGcGuc 141 GAGCUGGGAGGUCAGCGUC 401 AS 32 GACGCUGACCUCCcAGCUC 142 GACGCUGACCUCCCAGCUC 401 AD-20821 S 33 GuGGccAGuuuGGcuucuG 143 GUGGCCAGUUUGGCUUCUG 1744 AS 34 cAGAAGCcAAACUGGCcAC 144 CAGAAGCCAAACUGGCCAC 1744 AD-20822 S 35 cAGuuuGGcuucuGGAuGG 145 CAGUUUGGCUUCUGGAUGG 1749 AS 36 CcAUCcAGAAGCcAAACUG 146 CCAUCCAGAAGCCAAACUG 1749 AD-20823 s 37 GGccAGuuuGGcuucuGGA 147 GGCCAGUUUGGCUUCUGGA 1746 AS 38 UCcAGAAGCcAAACUGGCC 148 UCCAGAAGCCAAACUGGCC 1746 AD-20824 s 39 cuGGGuGGccAGuuuGGcu 149 CUGGGUGGCCAGUUUGGCU 1740 AS 40 AGCcAAACUGGCcACCcAG 150 AGCCAAACUGGCCACCCAG 1740 AD-20825 S 41 ucuAcAGuGAcuAcAAcAc 151 UCUACAGUGACUACAACAC 1294 AS 42 GUGUUGuAGUcACUGuAGA 152 GUGUUGUAGUCACUGUAGA 1294 AD-20826 S 43 GcAuGAcAGAGAAGGcAcu 153 GCAUGACAGAGAAGGCACU 1009 AS 44 AGUGCCUUCUCUGUcAUGC 154 AGUGCCUUCUCUGUCAUGC 1009 AD-20827 S 45 AuAucAcccuGAGcAGGAA 155 AUAUCACCCUGAGCAGGAA 1627 AS 46 UUCCUGCUcAGGGUGAuAU 156 UUCCUGCUCAGGGUGAUAU 1627 AD-20828 S 47 cuAcAGuGAcuAcAAcAcG 157 CUACAGUGACUACAACACG 1295 AS 48 CGUGUUGuAGUcACUGuAG 158 CGUGUUGUAGUCACUGUAG 1295 AD-20829 S 49 uAucAcccuGAGcAGGAAG 159 UAUCACCCUGAGCAGGAAG 1628 AS 50 CUUCCUGCUcAGGGUGAuA 160 CUUCCUGCUCAGGGUGAUA 1628 AD-20830 S 51 uGcAGGccAccAAcAucuu 161 UGCAGGCCACCAACAUCUU 838 AS 52 AAGAUGUUGGUGGCCUGcA 162 AAGAUGUUGGUGGCCUGCA 838 AD-20831 S 53 cAuGAcAGAGAAGGcAcuu 163 CAUGACAGAGAAGGCACUU 1010 AS 54 AAGUGCCUUCUCUGUcAUG 164 AAGUGCCUUCUCUGUCAUG 1010 AD-20832 S 55 uGAAGAAGuAccuGcuGAA 165 UGAAGAAGUACCUGCUGAA 184 AS 56 UUcAGcAGGuACUUCUUcA 166 UUCAGCAGGUACUUCUUCA 184 AD-20833 S 57 GcuGGuGGAGGcccAcAcc 167 GCUGGUGGAGGCCCACACC 1916 •153· 154740.doc 201141489 AS 58 GGUGUGGGCCUCcACcAGC 168 GGUGUGGGCCUCCACCAGC 1916 AD-20834 S 59 uAcAGuGAcuAcAAcAcGA 169 UACAGUGACUACAACACGA 1296 AS 60 UCGUGUUGuAGUcACUGuA 170 UCGUGUUGUAGUCACUGUA 1296 AD-20835 S 61 AcAGAGAAGGcAcuuccuu 171 ACAGAGAAGGCACUUCCUU 1014 AS 62 AAGGAAGUGCCUUCUCUG U 172 AAGGAAGUGCCUUCUCUGU 1014 AD-20836 S 63 AcAGuGAcuAcAAcAcGAc 173 ACAGUGACUACAACACGAC 1297 AS 64 GUCGUGUUGuAGUcACUGU 174 GUCGUGUUGUAGUCACUGU 1297 AD-20837 S 65 uGAGcuGGGAGGucAGcGu 175 UGAGCUGGGAGGUCAGCGU 400 AS 66 ACGCUGACCUCCcAGCUcA 176 ACGCUGACCUCCCAGCUCA 400 AD-20838 S 67 uGGccAGuuuGGcuucuGG 177 UGGCCAGUUUGGCUUCUGG 1745 AS 68 CcAGAAGCcAAACUGGCcA 178 CCAGAAGCCAAACUGGCCA 1745 AD-20839 S 69 uGucucAGGAGcGGGAccA 179 UGUCUCAGGAGCGGGACCA 1600 AS 70 UGGUCCCGCUCCUGAGAcA 180 UGGUCCCGCUCCUGAGACA 1600 AD-20840 S 71 GuGGAGGcccAcAccAAcu 181 GUGGAGGCCCACACCAACU 1920 AS 72 AGUUGGUGUGGGCCUCcAC 182 AGUUGGUGUGGGCCUCCAC 1920 AD-20841 S 73 GGGuGGccAGuuuGGcuuc 183 GGGUGGCCAGUUUGGCUUC 1742 AS 74 GAAGCcAAACUGGCcACCC 184 GAAGCCAAACUGGCCACCC 1742 AD-20842 S 75 GGuGGccAGuuuGGcuucu 185 GGUGGCCAGUUUGGCUUCU 1743 AS 76 AGAAGCcAAACUGGCcACC 186 AGAAGCCAAACUGGCCACC 1743 AD-20843 S 77 ucAcccuGAGcAGGAAGGG 187 UCACCCUGAGCAGGAAGGG 1630 AS 78 CCCUUCCUGCUcAGGGUGA 188 CCCUUCCUGCUCAGGGUGA 1630 AD-20844 s 79 GccAGuuuGGcuucuGGAu 189 GCCAGUUUGGCUUCUGGAU 1747 AS 80 AUCcAGAAGCcAAACUGGC 190 AUCCAGAAGCCAAACUGGC 1747 AD-20845 s 81 AGcuGGuGGAGGcccAcAc 191 AGCUGGUGGAGGCCCACAC 1915 AS 82 GUGUGGGCCUCcACcAGCU 192 GUGUGGGCCUCCACCAGCU 1915 AD-20846 S 83 AucuccAuGGcuGAcuGGc 193 AUCUCCAUGGCUGACUGGC 1545 AS 84 GCcAGUcAGCcAUGGAGAU 194 GCCAGUCAGCCAUGGAGAU 1545 AD-20847 S 85 GGcAuGAcAGAGAAGGcAc 195 GGCAUGACAGAGAAGGCAC 1008 AS 86 GUGCCUUCUCUGUcAUGCC 196 GUGCCUUCUCUGUCAUGCC 1008 AD-20848 S 87 GGAGAAAuAcuGcAAcAAc 197 GGAGAAAUACUGCAACAAC 1409 AS 88 GUUGUUGcAGuAUUUCUCC 198 GUUGUUGCAGUAUUUCUCC 1409 AD-20849 S 89 uGGGuGGccAGuuuGGcuu 199 UGGGUGGCCAGUUUGGCUU 1741 AS 90 AAGCcAAACUGGCcACCcA 200 AAGCCAAACUGGCCACCCA 1741 AD-20850 S 91 GAGcuGGuGGAGGcccAcA 201 GAGCUGGUGGAGGCCCACA 1914 AS 92 UGUGGGCCUCcACcAGCUC 202 UGUGGGCCUCCACCAGCUC 1914 AD-20851 S 93 GAcAGAGAAGGcAcuuccu 203 GACAGAGAAGGCACUUCCU 1013 AS 94 AGGAAGUGCCUUCUCUGUC 204 AGGAAGUGCCUUCUCUGUC 1013 AD-20852 S 95 AGuuuGGcuucuGGAuGGG 205 AGUUUGGCUUCUGGAUGGG 1750 AS 96 CCcAUCcAGAAGCcAAACU 206 CCCAUCCAGAAGCCAAACU 1750 AD-20861 S 97 uGAcAGAGAAGGcAcuucc 207 UGACAGAGAAGGCACUUCC 1012 AS 98 GGAAGUGCCUUCUCUGUcA 208 GGAAGUGCCUUCUCUGUCA 1012 AD-20862 S 99 G AA G AA G u Accu Gcu G AA G 209 GAAGAAGUACCUGCUGAAG 185 AS 100 CUUcAGcAGGuACUUCUUC 210 CUUCAGCAGGUACUUCUUC 185 AD-20863 S 101 ucuccAuGGcuGAcuGGcc 211 UCUCCAUGGCUGACUGGCC 1546 AS 102 GGCcAGUcAGCcAUGGAGA 212 GGCCAGUCAGCCAUGGAGA 1546 AD-20864 S 103 cuGGuGGAGGcccAcAccA 213 CUGGUGGAGGCCCACACCA 1917 AS 104 UGGUGUGGGCCUCcACcAG 214 UGGUGUGGGCCUCCACCAG 1917 AD-20865 S 105 cAGAGAAGGcAcuuccuuc 215 CAGAGAAGGCACUUCCUUC 1015 AS 106 GAAGGAAGUGCCUUCUCUG 216 GAAGGAAGUGCCUUCUCUG 1015 AD-20866 s 107 cuGcAGGccAccAAcAucu 217 CUGCAGGCCACCAACAUCU 837 AS 108 AGAUGUUGGUGGCCUGcAG 218 AGAUGUUGGUGGCCUGCAG 837 AD-20867 S 109 GGGcAuGAcAGAGAAGGcA 219 GGGCAUGACAGAGAAGGCA 1007 AS no UGCCUUCUCUGUcAUGCCC 220 UGCCUUCUCUGUCAUGCCC 1007Duplex ID SEQ ID Modified sequence SEQ ID Unmodified sequence Pos'n AD-20805 S 1 c AGu G Acu Ac AAc AcG Acc 111 CAGUGACUACAACACGACC 1298 AS 2 GGUCGUGUUGuAGUcACUG 112 GGUCGUGUUGUAGUCACUG 1298 AD-20806 S 3 AuGAcAGAGAAGGcAcuuc 113 AUGACAGAGAAGGCACUUC 1011 AS 4 GAAGUGCCUUCUCUGUcAU 114 GAAGUGCCUUCUCUGUCAU 1011 AD-20807 S 5 GuGAAGAAGuAccuGcuGA 115 GUGAAGAAGUACCUGCUGA 183 AS 6 UcAGcAGGuACUUCUUcAC 116 UCAGCAGGUACUUCUUCAC 183 AD-20808 S 7 GuGAcuAcAAcAcGAccuA 117 GUGACUACAACACGACCUA 1300 AS 8 uAGGUCGUGUUGuAGUcAC 118 uAGGUCGUGUUGUAGUCAC 1300 AD-20809 S 9 GGuGGAGGcccAcAccAAc 119 GGUGGAGGCCCACACCAAC 1919 AS 10 GUUGGUGUGGGCCUCcACC 120 GUUGGUGUGGGCCUCCACC 1919 AD-20810 S 11 uGGuGGAGGcccAcAccAA 121 uGGUGGAGGCCCACACCAA 1918 AS 12 UUGGUGUGGGCCUCcACcA 122 UUGGUGUGGGCCUCCACCA 1918 AD-20811 S 13 uuccAAGAccAcAuGAucc 123 uUCCAAGACCACAUGAUCC 1347 AS 14 GGAUcAUGUGGUCUUGGAA 124 GGAUCAUGUGGUCUUGGAA 1347 AD-20812 S 15 AGcuGGGAGGucAGcGucu 125 AGCUGGGAGGUCAGCGUCU 402 AS 16 AGACGCUGACCUCCcAGC U 126 AGACGCUGACCUCCCAGCU 402 AD-20813 S 17 GGGAGAAAuAcuGcAAcAA 127 GGGAGAAAUACUGCAACAA 1408 AS 18 UUGUUGcAGuAUUUCUCCC 128 UUGUUGCAGUAUUUCUCCC 1408 AD-20814 S 19 ccAGuuuGGcuucuGGAuG 129 CCAGUUUGGCUUCUGGAUG 1748 AS 20 cAUCcAGAAGCcAAACUGG 130 CAUCCAGAAGCCAAACUGG 1748 AD-20815 S 21 AGuGAcuAcAAcAcGAccu 131 AGUGACUACAACACGACCU 1299 AS 22 AGGUCGUGUUGuAGUcACU 132 AGGUCGUGUUGUAGUCACU 1299 AD -20816 S 23 AAuAucAcccuGAGcAGGA 133 AAUAUCACCCUGAGCAGGA 1626 AS 24 UCCUGCUcAGGGUGAuAUU 134 UCCUGCUCAGGGUGAUAUU 1626 AD-20817 S 25 ccuGcAGGccAccAAcAuc 135 CCUGCAGGCCACCAACAUC 836 AS 26 GAUGUUGGUGGCCUGcAGG 136 GAUGUUGGUGGCCUGCAGG 836 AD-20818 s 27 AucAcccuGAGcAGGAAGG 137 AUCACCCUGAGCAGGAAGG 1629 AS 28 CCUUCCUGCUcAGGGUGAU 138 CCUUCCUGCUCAGGGUGAU 1629 AD-20819 s 29 GcuGGGAGGucAGcGucuc 139 GCUGGGAGGUCAGCGUCUC 403 AS 30 GAGACGCUGACCUCCcAGC 140 GAGACGCUGACCUCCCAGC 403 AD-20820 s 31 GAGcuGGGAGGucAGcGuc 141 GAGCUGGGAGGUCAGCGUC 401 AS 32 GACGCUGACCUCCcAGCUC 142 GACGCUGACCUCCCAGCUC 401 AD-2082 1 S 33 GuGGccAGuuuGGcuucuG 143 GUGGCCAGUUUGGCUUCUG 1744 AS 34 cAGAAGCcAAACUGGCcAC 144 CAGAAGCCAAACUGGCCAC 1744 AD-20822 S 35 cAGuuuGGcuucuGGAuGG 145 CAGUUUGGCUUCUGGAUGG 1749 AS 36 CcAUCcAGAAGCcAAACUG 146 CCAUCCAGAAGCCAAACUG 1749 AD-20823 s 37 GGccAGuuuGGcuucuGGA 147 GGCCAGUUUGGCUUCUGGA 1746 AS 38 UCcAGAAGCcAAACUGGCC 148 UCCAGAAGCCAAACUGGCC 1746 AD-20824 s 39 cuGGGuGGccAGuuuGGcu 149 CUGGGUGGCCAGUUUGGCU 150 AGCCAAACUGGCCACCCAG 1740 AD-20825 S 41 ucuAcAGuGAcuAcAAcAc 1740 AS 40 AGCcAAACUGGCcACCcAG 151 UCUACAGUGACUACAACAC 1294 AS 42 GUGUUGuAGUcACUGuAGA 152 GUGUUGUAGUCACUGUAGA 1294 AD-20826 S 43 GcAuGAcAGAGAAGGcAcu 153 GCAUGACAGAGAAGGCACU 1009 AS 44 AGUGCCUUCUCUGUcAUGC 154 AGUGCCUUCUCUGUCAUGC 1009 AD-20827 S 45 AuAucAcccuGAGcAGGAA 155 AUAUCACCCUGAGCAGGAA 1627 AS 46 UUCCUGCUcAGGGUGAuAU 156 UUCCUGCUCAGGGUGAUAU 1627 AD-20828 S 47 cuAcAGuGAcuAcAAcAcG 157 CUACAGUGACUACAACACG 1295 AS 48 CGUGUUGuAGUcACUGuAG 158 CGUGUUGUAGUCACUGUAG 1295 AD-20829 S 49 uAucAcccuGAGcAGGAAG 159 U AUCACCCUGAGCAGGAAG 1628 AS 50 CUUCCUGCUcAGGGUGAuA 160 CUUCCUGCUCAGGGUGAUA 1628 AD-20830 S 51 uGcAGGccAccAAcAucuu 161 UGCAGGCCACCAACAUCUU 838 AS 52 AAGAUGUUGGUGGCCUGcA 162 AAGAUGUUGGUGGCCUGCA 838 AD-20831 S 53 cAuGAcAGAGAAGGcAcuu 163 CAUGACAGAGAAGGCACUU 1010 AS 54 AAGUGCCUUCUCUGUcAUG 164 AAGUGCCUUCUCUGUCAUG 1010 AD-20832 S 55 uGAAGAAGuAccuGcuGAA 165 UGAAGAAGUACCUGCUGAA 184 AS 56 UUcAGcAGGuACUUCUUcA 166 UUCAGCAGGUACUUCUUCA 184 AD-20833 S 57 GcuGGuGGAGGcccAcAcc 167 GCUGGUGGAGGCCCACACC 1916 • 153 · 154740.doc 201141489 AS 58 GGUGUGGGCCUCcACcAGC 168 GGUGUGGGCCUCCACCAGC 1916 AD-20834 S 59 uAcAGuGAcuAcAAcAcGA 169 UACAGUGACUACAACACGA 1296 AS 60 UCGUGUUGuAGUcACUGuA 170 UCGUGUUGUAGUCACUGUA 1296 AD-20835 S 61 AcAGAGAAGGcAcuuccuu 171 ACAGAGAAGGCACUUCCUU 1014 AS 62 AAGGAAGUGCCUUCUCUG U 172 AAGGAAGUGCCUUCUCUGU 1014 AD-20836 S 63 AcAGuGAcuAcAAcAcGAc 173 ACAGUGACUACAACACGAC 1297 AS 64 GUCGUGUUGuAGUcACUGU 174 GUCGUGUUGUAGUCACUGU 1297 AD-20837 S 65 uGAGcuGGGAGGucAGcGu 175 UGAGCUGG GAGGUCAGCGU 400 AS 66 ACGCUGACCUCCcAGCUcA 176 ACGCUGACCUCCCAGCUCA 400 AD-20838 S 67 uGGccAGuuuGGcuucuGG 177 UGGCCAGUUUGGCUUCUGG 1745 AS 68 CcAGAAGCcAAACUGGCcA 178 CCAGAAGCCAAACUGGCCA 1745 AD-20839 S 69 uGucucAGGAGcGGGAccA 179 UGUCUCAGGAGCGGGACCA 1600 AS 70 UGGUCCCGCUCCUGAGAcA 180 UGGUCCCGCUCCUGAGACA 1600 AD-20840 S 71 GuGGAGGcccAcAccAAcu 181 GUGGAGGCCCACACCAACU 1920 AS 72 AGUUGGUGUGGGCCUCcAC 182 AGUUGGUGUGGGCCUCCAC 1920 AD-20841 S 73 GGGuGGccAGuuuGGcuuc 183 GGGUGGCCAGUUUGGCUUC 1742 AS 74 GAAGCcAAACUGGCcACCC 184 GAAGCCAAACUGGCCACCC 1742 AD-20842 S 75 GGuGGccAGuuuGGcuucu 185 GGUGGCCAGUUUGGCUUCU 1743 AS 76 AGAAGCcAAACUGGCcACC 186 AGAAGCCAAACUGGCCACC 1743 AD-20843 S 77 ucAcccuGAGcAGGAAGGG 187 uCACCCUGAGCAGGAAGGG 1630 AS 78 CCCUUCCUGCUcAGGGUGA 188 CCCUUCCUGCUCAGGGUGA 1630 AD- 20844 s 79 GccAGuuuGGcuucuGGAu 189 GCCAGUUUGGCUUCUGGAU 1747 AS 80 AUCcAGAAGCcAAACUGGC 190 AUCCAGAAGCCAAACUGGC 1747 AD-20845 s 81 AGcuGGuGGAGGcccAcAc 191 AGCUGGUGGAGGCCCACAC 1915 AS 82 GUGUGGGCC UCcACcAGCU 192 GUGUGGGCCUCCACCAGCU 1915 AD-20846 S 83 AucuccAuGGcuGAcuGGc 193 AUCUCCAUGGCUGACUGGC 1545 AS 84 GCcAGUcAGCcAUGGAGAU 194 GCCAGUCAGCCAUGGAGAU 1545 AD-20847 S 85 GGcAuGAcAGAGAAGGcAc 195 GGCAUGACAGAGAAGGCAC 1008 AS 86 GUGCCUUCUCUGUcAUGCC 196 GUGCCUUCUCUGUCAUGCC 1008 AD-20848 S 87 GGAGAAAuAcuGcAAcAAc 197 GGAGAAAUACUGCAACAAC 1409 AS 88 GUUGUUGcAGuAUUUCUCC 198 GUUGUUGCAGUAUUUCUCC 1409 AD -20849 S 89 uGGGuGGccAGuuuGGcuu 199 UGGGUGGCCAGUUUGGCUU 1741 AS 90 AAGCcAAACUGGCcACCcA 200 AAGCCAAACUGGCCACCCA 1741 AD-20850 S 91 GAGcuGGuGGAGGcccAcA 201 GAGCUGGUGGAGGCCCACA 1914 AS 92 UGUGGGCCUCcACcAGCUC 202 UGUGGGCCUCCACCAGCUC 1914 AD-20851 S 93 GAcAGAGAAGGcAcuuccu 203 GACAGAGAAGGCACUUCCU 1013 AS 94 AGGAAGUGCCUUCUCUGUC 204 AGGAAGUGCCUUCUCUGUC 1013 AD-20852 S 95 AGuuuGGcuucuGGAuGGG 205 AGUUUGGCUUCUGGAUGGG 1750 AS 96 CCcAUCcAGAAGCcAAACU 206 CCCAUCCAGAAGCCAAACU 1750 AD-20861 S 97 uGAcAGAGAAGGcAcuucc 207 UGACAGAGAAGGCACUUCC 1012 AS 98 GGAAGUGCCUUCUCUGUCA 208 GGAAGUGCCUUCUCUGU CA 1012 AD-20862 S 99 G AA G AA G u Accu Gcu G AA G 209 GAAGAAGUACCUGCUGAAG 185 AS 100 CUUcAGcAGGuACUUCUUC 210 CUUCAGCAGGUACUUCUUC 185 AD-20863 S 101 ucuccAuGGcuGAcuGGcc 211 UCUCCAUGGCUGACUGGCC 1546 AS 102 GGCcAGUcAGCcAUGGAGA 212 GGCCAGUCAGCCAUGGAGA 1546 AD-20864 S 103 cuGGuGGAGGcccAcAccA 213 CUGGUGGAGGCCCACACCA 1917 AS 104 UGGUGUGGGCCUCcACcAG 214 UGGUGUGGGCCUCCACCAG 1917 AD-20865 S 105 cAGAGAAGGcAcuuccuuc 215 CAGAGAAGGCACUUCCUUC 1015 AS 106 GAAGGAAGUGCCUUCUCUG 216 GAAGGAAGUGCCUUCUCUG 1015 AD-20866 s 107 cuGcAGGccAccAAcAucu 217 CUGCAGGCCACCAACAUCU 837 AS 108 AGAUGUUGGUGGCCUGcAG 218 AGAUGUUGGUGGCCUGCAG 837 AD-20867 S 109 GGGcAuGAcAGAGAAGGcA 219 GGGCAUGACAGAGAAGGCA 1007 AS no UGCCUUCUCUGUcAUGCCC 220 UGCCUUCUCUGUCAUGCCC 1007

熟習此項技術者容易構想SEQ ID NO: 111至220之RNAi 劑之序列的修飾。構想此等序列之實例及非限制性修飾且 亦列於表1中，例如SEQ ID NO: 1至110中之有義及反義 (AS)序列。 154740.doc -154- 201141489 一些修飾置於預測對核酸内切酶敏感之位點。一些修飾 經設計以消除對siRNA之免疫反應，同時保留活性。一般 而言’有義股大量修飾，且反義股稍微修飾。一些修飾用 於一種以上目的。 表1中及其他表之序列由此等縮寫表示： 表1A.縮寫 縮寫 核苷酸 — A 腺苷-5'-磷酸酯 -- C 胞苷-5〜磷酸醋 ~ G 鳥苷-5'-磷酸酯 ~~ dT 2^去氧-胸苷-5'-蛾酸酯 — U 尿芽-5'-磷酸酯 c 20-甲基胞苷-5'-碟酸酯 — u 2'-0-曱基尿苷-51-填酸酯 · sdT 2'-去氧胸苷硫代磷酸酯 - siRNA序列選擇Modifications of the sequences of the RNAi agents of SEQ ID NOs: 111 to 220 are readily contemplated by those skilled in the art. Examples and non-limiting modifications of such sequences are contemplated and are also listed in Table 1, such as the sense and antisense (AS) sequences of SEQ ID NOs: 1 to 110. 154740.doc -154- 201141489 Some modifications are placed at sites predicted to be sensitive to endonucleases. Some modifications are designed to eliminate the immune response to siRNA while retaining activity. In general, the right-handed stocks are heavily modified and the antisense stocks are slightly modified. Some modifications are used for more than one purpose. The sequences in Table 1 and other tables are represented by such abbreviations: Table 1A. Abbreviated abbreviated nucleotides - A adenosine-5'-phosphate--C cytidine-5~phosphate vinegar~ G guanosine-5'- Phosphate ~~ dT 2^deoxy-thymidine-5'-mothate - U urinary bud-5'-phosphate c 20-methylcytidine-5'-dissolvate - u 2'-0- Thioglycol-51-filler·sdT 2'-deoxythymidine phosphorothioate - siRNA sequence selection

如貫例2中所述’合成總計55個有義及55個反義人類 SCNNB1源siRNA寡聚物（針對β-ENaC之RNAi劑）。有義寡 聚物及其各別反義寡聚物黏接於雙鏈體。A total of 55 sense and 55 antisense human SCNNB1 derived siRNA oligos (RNAi agents against β-ENaC) were synthesized as described in Example 2. The sense oligomer and its individual antisense oligomers are attached to the duplex.

實例1A Ρ-ENaC RNAi劑之重疊組 本發明亦係關於具有重疊序列之針對p_ENac之RNAi劑 的組。因此，本發明涵蓋RNAi劑之組，其中組中之各 RNAi劑與同一組中之各其他RNAi劑重疊至少5、6、7、 8、 9、 10、 11、 12、 13、 14、 15、 16、 17、 18、 19或19個 以上核苷酸。特定言之，在一實施例中，重疊為至少12個 nt 〇 15474D.doc 155- 201141489 本文所列之一些RNAi劑的序列彼此重疊。表2呈現重疊 RNAi劑之此等組中之一些的彙編，其中組之各成員與同 一組中之各其他成員重疊至少12個nt。呈現有義股及反義 股之12個nt重疊部分。 因此，舉例而言，如表2所示，RNAi劑AD-20807及AD-20832 之序 列重疊 ，其 中有義 股中之 重疊包 含序列 UGAAGAAGUACC(SEQ ID NO: 223);此等 RNAi劑的反義 股序列亦重疊，其中重疊包含序列GGUACUUCUUCA(SEQ ID NO: 224)。RNAi劑 AD-20807、AD-20862及 AD-20832均 在有義股中重疊，其中重疊包含序列GAAGAAGUACCU (SEQ ID NO: 225);此等RNAi劑之反義股亦重疊，其中重 疊包含序列 AGGUACUUCUUC(SEQ ID NO: 226)。因此， 表2所呈現之重疊RNAi劑之此等及其他多個組共有常見技 術特徵，例如有義股及反義股中之重疊。 下表2中提供針對β-ENaC之重疊RNAi劑的特定組。 本發明因此涵蓋包含常見技術特徵之RNAi劑的任何組 或子組，其中常見技術特徵為有義股或反義股中之序列重 疊（例如至少12個nt)。 表2.EXAMPLE 1A Overlapping Sets of Ρ-ENaC RNAi Agents The present invention is also directed to a group of RNAi agents against p_ENac having overlapping sequences. Accordingly, the invention encompasses a group of RNAi agents, wherein each RNAi agent in the group overlaps with each other RNAi agent in the same group by at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more nucleotides. In particular, in one embodiment, the overlap is at least 12 nt 〇 15474D.doc 155- 201141489 The sequences of some of the RNAi agents listed herein overlap each other. Table 2 presents a compilation of some of these groups of overlapping RNAi agents, with each member of the group overlapping at least 12 nt with each other member of the same group. Presents 12 nt overlapping parts of the stock and antisense stocks. Thus, for example, as shown in Table 2, the sequences of the RNAi agents AD-20807 and AD-20832 overlap, wherein the overlap in the sense strand comprises the sequence UGAGAGAGUACC (SEQ ID NO: 223); antisense of these RNAi agents The strand sequences also overlap, wherein the overlap comprises the sequence GGACAPUCUUCIA (SEQ ID NO: 224). The RNAi agents AD-20807, AD-20862 and AD-20832 overlap in the sense strand, wherein the overlap comprises the sequence GAAGAAGUACCU (SEQ ID NO: 225); the antisense strands of these RNAi agents also overlap, wherein the overlap comprises the sequence AGGUACUUCUUC (SEQ ID NO: 226). Thus, these and other groups of overlapping RNAi agents presented in Table 2 share common technical features, such as overlap in the sense and antisense strands. Specific groups of overlapping RNAi agents for β-ENaC are provided in Table 2 below. The invention thus encompasses any group or subgroup of RNAi agents comprising common technical features, wherein a common technical feature is that the sequences in the sense strand or the antisense strand overlap (e.g., at least 12 nt). Table 2.

Pos 有義重4 SEQ ID 反義重疊 SEQ ID 針對β-ENaC之重疊RNAi劑 183 UGAAGAAGUACC 223 GGUACUUCUUCA 224 AD-20807 ' AD-20832 184 GAAGAAGUACCU 225 AGGUACUUCUUC 226 AD-20807、AD-20862、 AD-20832 185 AAGAAGUACCUG 227 CAGGUACUUCUU 228 AD-20807、AD-20862、 AD-20832 186 AGAAGUACCUGC 229 GCAGGUACUUCU 230 AD-20807 ' AD-20862 ' AD-20832 187 GAAGUACCUGCU 231 AGCAGGUACUUC 232 AD-20807、AD-20862、 AD-20832 154740.doc •156· 201141489Pos sense weight 4 SEQ ID antisense overlap SEQ ID overlap RNAi agent for β-ENaC 183 UGAAGAAGUACC 223 GGUACUUCUUCA 224 AD-20807 ' AD-20832 184 GAAGAAGUACCU 225 AGGUACUUCUUC 226 AD-20807, AD-20862, AD-20832 185 AAGAAGUACCUG 227 CAGGUACUUCUU 228 AD-20807, AD-20862, AD-20832 186 AGAAGUACCUGC 229 GCAGGUACUUCU 230 AD-20807 'AD-20862 ' AD-20832 187 GAAGUACCUGCU 231 AGCAGGUACUUC 232 AD-20807, AD-20862, AD-20832 154740.doc •156 · 201141489

188 AAGUACCUGCUG 233 CAGCAGGUACUU 234 AD-20807 ^ AD-20862 ^ AD-20832 189 AGUACCUGCUGA 235 UCAGCAGGUACU 236 AD-20807 - AD-20862 &gt; AD-20832 190 GUACCUGCUGAA 237 UUCAGCAGGUAC 238 AD-20862、AD-20832 400 GAGCUGGGAGGU 239 ACCUCCCAGCUC 240 AD-20820、AD-20837 401 AGCUGGGAGGUC 241 GACCUCCCAGCU 242 AD-20820、AD-20812、 AD-20837 402 GCUGGGAGGUCA 243 UGACCUCCCAGC 244 AD-20820、AD-20819、 AD-20812 ' AD-20837 403 CUGGGAGGUCAG 245 CUGACCUCCCAG 246 AD-20819、AD-20812、 AD-20837 404 UGGGAGGUCAGC 247 GCUGACCUCCCA 248 AD-20820、AD-20819、 AD-20837 405 GGGAGGUCAGCG 249 CGCUGACCUCCC 250 AD-20820、AD-20819、 AD-20812、AD-20837 406 GGAGGUCAGCGU 251 ACGCUGACCUCC 252 AD-20819、AD-20837 407 GAGGUCAGCGUC 253 GACGCUGACCUC 254 AD-20820、AD-20819、 AD-20812 408 AGGUCAGCGUCU 255 AGACGCUGACCU 256 AD-20819 ' AD-20812 836 CUGCAGGCCACC 257 GGUGGCCUGCAG 258 AD-20866 ' AD-20817 837 UGCAGGCCACCA 259 UGGUGGCCUGCA 260 AD-20866、AD-20830、 AD-20817 838 GCAGGCCACCAA 261 UUGGUGGCCUGC 262 AD-20866、AD-20830、 AD-20817 839 CAGGCCACCAAC 263 GUUGGUGGCCUG 264 AD-20866 ' AD-20830 ' AD-20817 840 AGGCCACCAACA 265 UGUUGGUGGCCU 266 AD-20866、AD-20830、 AD-20817 841 GGCCACCAACAU 267 AUGUUGGUGGCC 268 AD-20866、AD-20830、 AD-20817 842 GCCACCAACAUC 269 GAUGUUGGUGGC 270 AD-20866 ' AD-20830 ' AD-20817 843 CCACCAACAUCU 271 AGAUGUUGGUGG 272 AD-20866 ' AD-20830 1007 GGCAUGACAGAG 273 CUCUGUCAUGCC 274 AD-20847 ' AD-20867 1008 GCAUGACAGAGA 275 UCUCUGUCAUGC 276 AD-20826 ' AD-20867 1009 CAUGACAGAGAA 277 UUCUCUGUCAUG 278 AD-20826、AD-20831、 AD-20867 1010 AUGACAGAGAAG 279 CUUCUCUGUCAU 280 AD-20826、AD-20831、 AD-20867、AD-20806 1011 UGACAGAGAAGG 281 CCUUCUCUGUCA 282 AD-20826、AD-20831、 AD-20867、AD-20806、 AD-20861 1012 GACAGAGAAGGC 283 GCCUUCUCUGUC 284 AD-20851 ' AD-20847、 AD-20826、AD-20831、 AD-20867、AD-20806、 AD-20861 1013 ACAGAGAAGGCA 285 UGCCUUCUCUGU 286 AD-20851、AD-20835、 AD-20847、AD-20826、 AD-20831、AD-20867、 AD-20806 ' AD-20861 1014 CAGAGAAGGCAC 287 GUGCCUUCUCUG 288 AD-20851、AD-20835、 AD-20865、AD-20826、 AD-20831、AD-20806、 AD-20861 154740.doc •157- 201141489 1015 AGAGAAGGCACU 289 AGUGCCUUCUCU 290 AD-20851、AD-20835、 AD-20865、AD-20826、 AD-20831、AD-20806、 AD-20861 1016 GAGAAGGCACUU 291 AAGUGCCUUCUC 292 AD-20851、AD-20835、 AD-20865、AD-2083 卜 AD-20806、AD-20861 1017 AGAAGGCACUUC 293 GAAGUGCCUUCU 294 AD-20851 ' AD-20835 ' AD-20865、AD-20806、 AD-20861 1018 GAAGGCACUUCC 295 GGAAGUGCCUUC 296 AD-20851、AD-20835、 AD-20865 ' AD-20861 1019 AAGGCACUUCCU 297 AGGAAGUGCCUU 298 AD-20851、AD-20835、 AD-20865 1020 AGGCACUUCCUU 299 AAGGAAGUGCCU 300 AD-20835 ' AD-20865 1294 CUACAGUGACUA 301 UAGUCACUGUAG 302 AD-20828、AD-20825 1295 UACAGUGACUAC 303 GUAGUCACUGUA 304 AD-20834 ' AD-20825 1296 ACAGUGACUACA 305 UGUAGUCACUGU 306 AD-20828、AD-20834、 AD-20825、AD-20836 1297 CAGUGACUACAA 307 UUGUAGUCACUG 308 AD-20834、AD-20805、 AD-20825 1298 AGUGACUACAAC 309 GUUGUAGUCACU 310 AD-20828、AD-20834、 AD-20805、AD-20825、 AD-20836 1299 GUGACUACAACA 311 UGUUGUAGUCAC 312 AD-20834、AD-20805、 AD-20808 ' AD-20825 1300 UGACUACAACAC 313 GUGUUGUAGUCA 314 AD-20828、AD-20834、 AD-20805 ' AD-20808 &gt; AD-20825、AD-20815、 AD-20836 1301 GACUACAACACG 315 CGUGUUGUAGUC 316 AD-20828、AD-20834、 AD-20805、AD_20808、 AD-20836 1302 ACUACAACACGA 317 UCGUGUUGUAGU 318 AD-20834、AD-20805、 AD-20808 1303 CUACAACACGAC 319 GUCGUGUUGUAG 320 AD-20805、AD-20808、 AD-20815、AD-20836 1304 UACAACACGACC 321 GGUCGUGUUGUA 322 AD-20805、AD-20808 1305 ACAACACGACCU 323 AGGUCGUGUUGU 324 AD-20808、AD-20815 1408 GGAGAAAUACUG 325 CAGUAUUUCUCC 326 AD-20813 ' AD-20848 1409 GAGAAAUACUGC 327 GCAGUAUUUCUC 328 AD-20813 ' AD-20848 1410 AGAAAUACUGCA 329 UGCAGUAUUUCU 330 AD-20813、AD-20848 1411 GAAAUACUGCAA 331 UUGCAGUAUUUC 332 AD-20813、AD-20848 1412 AAAUACUGCAAC 333 GUUGCAGUAUUU 334 AD-20813、AD-20848 1413 AAUACUGCAACA 335 UGUUGCAGUAUU 336 AD-20813 ' AD-20848 1414 AUACUGCAACAA 337 UUGUUGCAGUAU 338 AD-20813 ' AD-20848 1545 UCUCCAUGGCUG 339 CAGCCAUGGAGA 340 AD-20846、AD-20863 1546 CUCCAUGGCUGA 341 UCAGCCAUGGAG 342 AD-20846、AD-20863 1547 UCCAUGGCUGAC 343 GUCAGCCAUGGA 344 AD-20846 ' AD-20863 1548 CCAUGGCUGACU 345 AGUCAGCCAUGG 346 AD-20846、AD-20863 1549 CAUGGCUGACUG 347 CAGUCAGCCAUG 348 AD-20846、AD-20863 1550 AUGGCUGACUGG 349 CCAGUCAGCCAU 350 AD-20846、AD-20863 1551 UGGCUGACUGGC 351 GCCAGUCAGCCA 352 AD-20846、AD-20863 1626 AUAUCACCCUGA 353 UCAGGGUGAUAU 354 AD-20816 ' AD-20827188 AAGUACCUGCUG 233 CAGCAGGUACUU 234 AD-20807 ^ AD-20862 ^ AD-20832 189 AGUACCUGCUGA 235 UCAGCAGGUACU 236 AD-20807 - AD-20862 &gt; AD-20832 190 GUACCUGCUGAA 237 UUCAGCAGGUAC 238 AD-20862, AD-20832 400 GAGCUGGGAGGU 239 ACCUCCCAGCUC 240 AD-20820, AD-20837 401 AGCUGGGAGGUC 241 GACCUCCCAGCU 242 AD-20820, AD-20812, AD-20837 402 GCUGGGAGGUCA 243 UGACCUCCCAGC 244 AD-20820, AD-20819, AD-20812 'AD-20837 403 CUGGGAGGUCAG 245 CUGACCUCCCAG 246 AD- 20819, AD-20812, AD-20837 404 UGGGAGGUCAGC 247 GCUGACCUCCCA 248 AD-20820, AD-20819, AD-20837 405 GGGAGGUCAGCG 249 CGCUGACCUCCC 250 AD-20820, AD-20819, AD-20812, AD-20837 406 GGAGGUCAGCGU 251 ACGCUGACCUCC 252 AD-20819, AD-20837 407 GAGGUCAGCGUC 253 GACGCUGACCUC 254 AD-20820, AD-20819, AD-20812 408 AGGUCAGCGUCU 255 AGACGCUGACCU 256 AD-20819 'AD-20812 836 CUGCAGGCCACC 257 GGUGGCCUGCAG 258 AD-20866 ' AD-20817 837 UGCAGGCCACCA 259 UGGUGGCCUGCA 260 AD-20866, AD-20830, AD-20817 838 GCAGGCCACCAA 261 UUGGUGGCCUGC 262 AD-20 866, AD-20830, AD-20817 839 CAGGCCACCAAC 263 GUUGGUGGCCUG 264 AD-20866 'AD-20830' AD-20817 840 AGGCCACCAACA 265 UGUUGGUGGCCU 266 AD-20866, AD-20830, AD-20817 841 GGCCACCAACAU 267 AUGUUGGUGGCC 268 AD-20866, AD-20830, AD-20817 842 GCCACCAACAUC 269 GAUGUUGGUGGC 270 AD-20866 'AD-20830 ' AD-20817 843 CCACCAACAUCU 271 AGAUGUUGGUGG 272 AD-20866 ' AD-20830 1007 GGCAUGACAGAG 273 CUCUGUCAUGCC 274 AD-20847 ' AD-20867 1008 GCAUGACAGAGA 275 UCUCUGUCAUGC 276 AD-20826 ' AD-20867 1009 CAUGACAGAGAA 277 UUCUCUGUCAUG 278 AD-20826, AD-20831, AD-20867 1010 AUGACAGAGAAG 279 CUUCUCUGUCAU 280 AD-20826, AD-20831, AD-20867, AD-20806 1011 UGACAGAGAAGG 281 CCUUCUCUGUCA 282 AD-20826, AD-20831, AD-20867, AD-20806, AD-20861 1012 GACAGAGAAGGC 283 GCCUUCUCUGUC 284 AD-20851 'AD-20847, AD-20826, AD-20831, AD-20867, AD-20806, AD- 20861 1013 ACAGAGAAGGCA 285 UGCCUUCUCUGU 286 AD-20851, AD-20835, AD-20847, AD-20826, AD-20831, AD-20867, AD-20806 'AD-20861 1014 CAGAGAAGG CAC 287 GUGCCUUCUCUG 288 AD-20851, AD-20835, AD-20865, AD-20826, AD-20831, AD-20806, AD-20861 154740.doc • 157- 201141489 1015 AGAGAAGGCACU 289 AGUGCCUUCUCU 290 AD-20851, AD-20835 AD-20865, AD-20826, AD-20831, AD-20806, AD-20861 1016 GAGAAGGCACUU 291 AAGUGCCUUCUC 292 AD-20851, AD-20835, AD-20865, AD-2083 AD-20806, AD-20861 1017 AGAAGGCACUUC 293 GAAGUGCCUUCU 294 AD-20851 'AD-20835 ' AD-20865, AD-20806, AD-20861 1018 GAAGGCACUUCC 295 GGAAGUGCCUUC 296 AD-20851, AD-20835, AD-20865 ' AD-20861 1019 AAGGCACUUCCU 297 AGGAAGUGCCUU 298 AD-20851 AD-20835, AD-20865 1020 AGGCACUUCCUU 299 AAGGAAGUGCCU 300 AD-20835 ' AD-20865 1294 CUACAGUGACUA 301 UAGUCACUGUAG 302 AD-20828, AD-20825 1295 UACAGUGACUAC 303 GUAGUCACUGUA 304 AD-20834 ' AD-20825 1296 ACAGUGACUACA 305 UGUAGUCACUGU 306 AD -20828, AD-20834, AD-20825, AD-20836 1297 CAGUGACUACAA 307 UUGUAGUCACUG 308 AD-20834, AD-20805, AD-20825 1298 AGUGACUACAAC 309 GUUGUAGUCACU 310 AD-20828, AD-20834 AD-20805, AD-20825, AD-20836 1299 GUGACUACAACA 311 UGUUGUAGUCAC 312 AD-20834, AD-20805, AD-20808 'AD-20825 1300 UGACUACAACAC 313 GUGUUGUAGUCA 314 AD-20828, AD-20834, AD-20805 ' AD- 20808 &gt; AD-20825, AD-20815, AD-20836 1301 GACUACAACACG 315 CGUGUUGUAGUC 316 AD-20828, AD-20834, AD-20805, AD_20808, AD-20836 1302 ACUACAACACGA 317 UCGUGUUGUAGU 318 AD-20834, AD-20805, AD -20808 1303 CUACAACACGAC 319 GUCGUGUUGUAG 320 AD-20805, AD-20808, AD-20815, AD-20836 1304 UACAACACGACC 321 GGUCGUGUUGUA 322 AD-20805, AD-20808 1305 ACAACACGACCU 323 AGGUCGUGUUGU 324 AD-20808, AD-20815 1408 GGAGAAAUACUG 325 CAGUAUUUCUCC 326 AD-20813 ' AD-20848 1409 GAGAAAUACUGC 327 GCAGUAUUUCUC 328 AD-20813 ' AD-20848 1410 AGAAAUACUGCA 329 UGCAGUAUUUCU 330 AD-20813, AD-20848 1411 GAAAUACUGCAA 331 UUGCAGUAUUUC 332 AD-20813, AD-20848 1412 AAAUACUGCAAC 333 GUUGCAGUAUUU 334 AD -20813,AD-20848 1413 AAUACUGCAACA 335 UGUUGCAGUAUU 336 AD-20813 ' AD-20848 1414 AUACUGCAACAA 337 UUGUUGCAGU AU 338 AD-20813 ' AD-20848 1545 UCUCCAUGGCUG 339 CAGCCAUGGAGA 340 AD-20846, AD-20863 1546 CUCCAUGGCUGA 341 UCAGCCAUGGAG 342 AD-20846, AD-20863 1547 UCCAUGGCUGAC 343 GUCAGCCAUGGA 344 AD-20846 'AD-20863 1548 CCAUGGCUGACU 345 AGUCAGCCAUGG 346 AD-20846, AD-20863 1549 CAUGGCUGACUG 347 CAGUCAGCCAUG 348 AD-20846, AD-20863 1550 AUGGCUGACUGG 349 CCAGUCAGCCAU 350 AD-20846, AD-20863 1551 UGGCUGACUGGC 351 GCCAGUCAGCCA 352 AD-20846, AD-20863 1626 AUAUCACCCUGA 353 UCAGGGUGAUAU 354 AD- 20816 ' AD-20827

154740.doc -158- 201141489154740.doc -158- 201141489

1627 UAUCACCCUGAG 355 CUCAGGGUGAUA 356 AD-20816、AD-20827、 AD-20829 1628 AUCACCCUGAGC 357 GCUCAGGGUGAU 358 AD-20816、AD-20827、 AD-20829 ' AD-20818 1629 UCACCCUGAGCA 359 UGCUCAGGGUGA 360 AD-20816、AD-20827、 AD-20829、AD-20843、 AD-20818 1630 CACCCUGAGCAG 361 CUGCUCAGGGUG 362 AD-20816、AD-20827、 AD-20829、AD-20843、 AD-20818 1631 ACCCUGAGCAGG 363 CCUGCUCAGGGU 364 AD-20816、AD-20827、 AD-20829、AD-20843、 AD-20818 1632 CCCUGAGCAGGA 365 UCCUGCUCAGGG 366 AD-20816、AD-20827、 AD-20829 &gt; AD-20843 ' AD-20818 1633 CCUGAGCAGGAA 367 UUCCUGCUCAGG 368 AD-20827、AD-20829、 AD-20843 ' AD-20818 1634 CUGAGCAGGAAG 369 CUUCCUGCUCAG 370 AD-20829 &gt; AD-20843 ' AD-20818 1635 UGAGCAGGAAGG 371 CCUUCCUGCUCA 372 AD-20843、AD-20818 1740 UGGGUGGCCAGU 373 ACUGGCCACCCA 374 AD-20824 &gt; AD-20849 1741 GGGUGGCCAGUU 375 AACUGGCCACCC 376 AD-20824、AD-20841 ' AD-20849 1742 GGUGGCCAGUUU 377 AAACUGGCCACC 378 AD-20824、AD-20842、 AD-20841 ' AD-20849 1743 GUGGCCAGUUUG 379 CAAACUGGCCAC 380 AD-20824、AD-20842、 AD-20821、AD-20841、 AD-20849 1744 UGGCCAGUUUGG 381 CCAAACUGGCCA 382 AD-20824 ' AD-20842 ' AD-20821、AD-20838、 AD-20841 ' AD-20849 1745 GGCCAGUUUGGC 383 GCCAAACUGGCC 384 AD-20824、AD-20842、 AD-20821、AD-20838、 AD-20841 ' AD-20823 &gt; AD-20849 1746 GCCAGUUUGGCU 385 AGCCAAACUGGC 386 AD-20844、AD-20824、 AD-20842 ' AD-20821 ' AD-20838 ' AD-20841 ' AD-20823 ' AD-20849 1747 CCAGUUUGGCUU 387 AAGCCAAACUGG 388 AD-20814、AD-20844、 AD-20842、AD-20821、 AD-20838、AD-20841、 AD-20823 ' AD-20849 1748 CAGUUUGGCUUC 389 GAAGCCAAACUG 390 AD-20814、AD-20844、 AD-20842、AD-2082卜 AD-20838 ' AD-20841 ' AD-20822、AD-20823 1749 AGUUUGGCUUCU 391 AGAAGCCAAACU 392 AD-20814、AD-20844、 AD-20842 ' AD-20821 ' AD-20852 ' AD-20838 ' AD-20822、AD-20823 1750 GUUUGGCUUCUG 393 CAGAAGCCAAAC 394 AD-20814、AD-20844、 AD-20821、AD-20852、 AD-20838、AD-20822、 154740.doc -159- 201141489 AD-20823 1751 UUUGGCUUCUGG 395 CCAGAAGCCAAA 396 AD-20814、AD-20844、 AD-20852、AD-20838、 AD-20822 ' AD-20823 1752 UUGGCUUCUGGA 397 UCCAGAAGCCAA 398 AD-20814、AD-20844、 AD-20852、AD-20822、 AD-20823 1753 UGGCUUCUGGAU 399 AUCCAGAAGCCA 400 AD-20814、AD-20844、 AD-20852 ' AD-20822 1754 GGCUUCUGGAUG 401 CAUCCAGAAGCC 402 AD-20814、AD-20852、 AD-20822 1755 GCUUCUGGAUGG 403 CCAUCCAGAAGC 404 AD-20852、AD-20822 1914 AGCUGGUGGAGG 405 CCUCCACCAGCU 406 AD-20850、AD-20845 1915 GCUGGUGGAGGC 407 GCCUCCACCAGC 408 AD-20850、AD-20845、 AD-20833 1916 CUGGUGGAGGCC 409 GGCCUCCACCAG 410 AD-20850 ' AD-20845 ' AD-20833 ' AD-20864 1917 UGGUGGAGGCCC 411 GGGCCUCCACCA 412 AD-20810、AD-20850、 AD-20845、AD-20833、 AD-20864 1918 GGUGGAGGCCCA 413 UGGGCCUCCACC 414 AD-20809、AD-20810、 AD-20850 &gt; AD-20845 ' AD-20833、AD-20864 1919 GUGGAGGCCCAC 415 GUGGGCCUCCAC 416 AD-20809、AD-20810、 AD-20850、AD-20845、 AD-20833、AD-20864、 AD-20840 1920 UGGAGGCCCACA 417 UGUGGGCCUCCA 418 AD-20809、AD-20810、 AD-20850、AD-20845、 AD-20833、AD-20864、 AD-20840 1921 GGAGGCCCACAC 419 GUGUGGGCCUCC 420 AD-20809、AD-20810、 AD-20845、AD-20833、 AD-20864、AD-20840 1922 GAGGCCCACACC 421 GGUGUGGGCCUC 422 AD-20809、AD-20810、 AD-20833、AD-20864、 AD-20840 1923 AGGCCCACACCA 423 UGGUGUGGGCCU 424 AD-20809、AD-20810、 AD-20864 ' AD-20840 1924 GGCCCACACCAA 425 UUGGUGUGGGCC 426 AD-20809、AD-20810、 AD-20840 1925 GCCCACACCAAC 427 GUUGGUGUGGGC 428 AD-20809 &gt; AD-20840 指示NM_000336.2中之位置（「Pos」）。呈現有義及反義 股中12個例示性nt之重疊；在許多情形中，重疊實際上較 長。 實例2 合成P-ENaC RNAi劑序列 -160- 154740.doc 201141489 在MerMade 192合成器上以i μιη〇1規模合成如表itsEQ ID NO: 1至110所列之經修飾p_ENaC RNAi劑序列。 對於目錄中之所有序列’如下文詳述應用「」 化學。 」 有義股中之所有嘧啶（胞嘧啶及尿苷）含有2，_〇·曱基鹼基 (2’0-曱基C及2'-0-曱基U)。 在反義股中，與核糖A核苷相鄰（亦即朝向5，位置）之嘧啶 φ 換為其相應2-0-甲基核苷。 在有義序列及反義序列之3,端引入兩個鹼基dTsdT延 伸。 序列檔案轉化為文字檔案，以使其適於裝载至MerMade 192合成軟體中。 合成、裂解及脫除保護基： β-ENaC序列之合成使用固體支撐之寡核苷酸合成，其 使用胺基磷酸酯化學。1627 UAUCACCCUGAG 355 CUCAGGGUGAUA 356 AD-20816, AD-20827, AD-20829 1628 AUCACCCUGAGC 357 GCUCAGGGUGAU 358 AD-20816, AD-20827, AD-20829 ' AD-20818 1629 UCACCCUGAGCA 359 UGCUCAGGGUGA 360 AD-20816, AD-20827, AD -20829, AD-20843, AD-20818 1630 CACCCUGAGCAG 361 CUGCUCAGGGUG 362 AD-20816, AD-20827, AD-20829, AD-20843, AD-20818 1631 ACCCUGAGCAGG 363 CCUGCUCAGGGU 364 AD-20816, AD-20827, AD-20829 AD-20843, AD-20818 1632 CCCUGAGCAGGA 365 UCCUGCUCAGGG 366 AD-20816, AD-20827, AD-20829 &gt; AD-20843 'AD-20818 1633 CCUGAGCAGGAA 367 UUCCUGCUCAGG 368 AD-20827, AD-20829, AD-20843 ' AD-20818 1634 CUGAGCAGGAAG 369 CUUCCUGCUCAG 370 AD-20829 &gt; AD-20843 ' AD-20818 1635 UGAGCAGGAAGG 371 CCUUCCUGCUCA 372 AD-20843, AD-20818 1740 UGGGUGGCCAGU 373 ACUGGCCACCCA 374 AD-20824 &gt; AD-20849 1741 GGGUGGCCAGUU 375 AACUGGCCACCC 376 AD-20824, AD-20841 'AD-20849 1742 GGUGGCCAGUUU 377 AAACUGGCCACC 378 AD-20824, AD-20842, AD-20841 ' AD-20849 1743 GUGGCCAGUUUG 379 CAAACUG GCCAC 380 AD-20824, AD-20842, AD-20821, AD-20841, AD-20849 1744 UGGCCAGUUUGG 381 CCAAACUGGCCA 382 AD-20824 'AD-20842 'AD-20821, AD-20838, AD-20841 ' AD-20849 1745 GGCCAGUUUGGC 383 GCCAAACUGGCC 384 AD-20824, AD-20842, AD-20821, AD-20838, AD-20841 'AD-20823 &gt; AD-20849 1746 GCCAGUUUGGCU 385 AGCCAAACUGGC 386 AD-20844, AD-20824, AD-20842 'AD -20821 ' AD-20838 ' AD-20841 ' AD-20823 ' AD-20849 1747 CCAGUUUGGCUU 387 AAGCCAAACUGG 388 AD-20814, AD-20844, AD-20842, AD-20821, AD-20838, AD-20841, AD-20823 ' AD-20849 1748 CAGUUUGGCUUC 389 GAAGCCAAACUG 390 AD-20814, AD-20844, AD-20842, AD-2082 AD-20-20 'AD-20841 'AD-20822, AD-20823 1749 AGUUUGGCUUCU 391 AGAAGCCAAACU 392 AD-20814, AD -20844, AD-20842 'AD-20821 ' AD-20852 ' AD-20838 ' AD-20822, AD-20823 1750 GUUUGGCUUCUG 393 CAGAAGCCAAAC 394 AD-20814, AD-20844, AD-20821, AD-20852, AD-20838 , AD-20822, 154740.doc -159- 201141489 AD-20823 1751 UUUGGCUUCUGG 395 CCAGAAGCCAAA 396 AD-20814, AD-2 0844, AD-20852, AD-20838, AD-20822 'AD-20823 1752 UUGGCUUCUGGA 397 UCCAGAAGCCAA 398 AD-20814, AD-20844, AD-20852, AD-20822, AD-20823 1753 UGGCUUCUGGAU 399 AUCCAGAAGCCA 400 AD-20814, AD-20844, AD-20852 'AD-20822 1754 GGCUUCUGGAUG 401 CAUCCAGAAGCC 402 AD-20814, AD-20852, AD-20822 1755 GCUUCUGGAUGG 403 CCAUCCAGAAGC 404 AD-20852, AD-20822 1914 AGCUGGUGGAGG 405 CCUCCACCAGCU 406 AD-20850, AD- 20845 1915 GCUGGUGGAGGC 407 GCCUCCACCAGC 408 AD-20850, AD-20845, AD-20833 1916 CUGGUGGAGGCC 409 GGCCUCCACCAG 410 AD-20850 'AD-20845 'AD-20833 ' AD-20864 1917 UGGUGGAGGCCC 411 GGGCCUCCACCA 412 AD-20810, AD-20850, AD-20845, AD-20833, AD-20864 1918 GGUGGAGGCCCA 413 UGGGCCUCCACC 414 AD-20809, AD-20810, AD-20850 &gt; AD-20845 'AD-20833, AD-20864 1919 GUGGAGGCCCAC 415 GUGGGCCUCCAC 416 AD-20809, AD -20810, AD-20850, AD-20845, AD-20833, AD-20864, AD-20840 1920 UGGAGGCCCACA 417 UGUGGGCCUCCA 418 AD-20809, AD-20810, AD-20850, AD-20845, AD-20833, AD-2086 4. AD-20840 1921 GGAGGCCCACAC 419 GUGUGGGCCUCC 420 AD-20809, AD-20810, AD-20845, AD-20833, AD-20864, AD-20840 1922 GAGGCCCACACC 421 GGUGUGGGCCUC 422 AD-20809, AD-20810, AD-20833, AD-20864, AD-20840 1923 AGGCCCACACCA 423 UGGUGUGGGCCU 424 AD-20809, AD-20810, AD-20864 'AD-20840 1924 GGCCCACACCAA 425 UUGGUGUGGGCC 426 AD-20809, AD-20810, AD-20840 1925 GCCCACACCAAC 427 GUUGGUGUGGGC 428 AD- 20809 &gt; AD-20840 indicates the position in NM_000336.2 ("Pos"). Presenting an overlap of 12 exemplary nts in the sense and antisense stocks; in many cases, the overlap is actually longer. Example 2 Synthesis of P-ENaC RNAi Agent Sequence -160-154740.doc 201141489 A modified p_ENaC RNAi agent sequence as listed in its EQ ID NO: 1 to 110 was synthesized on a MerMade 192 synthesizer on the i μιη〇1 scale. For all sequences in the catalogue, the application of "" chemistry is detailed below. All pyrimidines (cytosine and uridine) in the sense strand contain 2, 〇 曱 bases (2'0-fluorenyl C and 2'-0-fluorenyl U). In the antisense strand, the pyrimidine φ adjacent to the ribose A nucleoside (i.e., towards the 5, position) is replaced by its corresponding 2-0-methyl nucleoside. Two base dTsdT extensions were introduced at the 3' end of the sense and antisense sequences. The sequence file is converted to a text file to make it suitable for loading into the MerMade 192 compositing software. Synthesis, cleavage and removal of protecting groups: The synthesis of the β-ENaC sequence was carried out using solid supported oligonucleotide synthesis using amino phosphate chemistry.

• 上述序列之合成以1 μηι規模在96孔板中進行。以〇」M 濃度製備amidite溶液且乙硫基四唑（乙腈中〇 6 M)用作活化 劑。 合成之序列在96孔板中裂解且脫除保護基，在第一步驟 中使用曱胺且在第二步驟中使用氟化物試劑。粗序列使用 丙鋼·乙醇（80.20)混合物沈j殿’且離心塊再懸浮於〇2 μ乙 酸鈉緩衝液中。藉由LC-MS分析來自各序列之樣品以確認 身分’ UV定量且所選樣品組藉由〗ΕΧ層析法測定純度。 純化及脫鹽： 154740.doc -161 - 201141489 在AKTA explorer純化系統上使用Source 15Q管柱純化β-ENaC序列。在純化期間保持65°C之管柱溫度。在96孔（1.8 mL深孔）板中進行樣品注射及收集。收集溶離劑中對應於 全長序列之單峰。經純化序列在Sephadex G25管柱上使用 AKTA純化器脫鹽。分析脫鹽之β-ENaC序列的濃度（藉由在 A260下UV量測）及純度（藉由離子交換HPLC)。 接著對單個股進行黏接。 β-ENaC單股及雙鏈體之詳細目錄顯示於上表1中。雙鏈 體用於活體外篩選以測試其阻斷β-ENaC基因含量的能力。 實例3. 活體外篩選P-ENaC RNAi劑 活體外篩選β-ENaC RNAi劑以測定其阻斷β-ENaC基因含 量之能力。 細胞培養及轉染： H441(ATCC，Manassas，VA)細胞在 37〇C 下在 5% C〇2氛圍 下在補充有10% FBS、鍵黴素（streptomycin)及麵酿胺酸 (ATCC)之RPMI 1640(ATCC)中生長至接近匯合，隨後藉由 胰蛋白酶處理自板釋放。反轉染藉由將5 μΐ Opti-MEM與 每孔 10 μΐ Opti-MEM加 0.2 μΐ脂染胺 RNAiMax(Invitrogen， Carlsbad CA.目錄號13778-150)—起添加至96孔板中每孔5 μΐ siRNA雙鏈體申，且在室溫下培育15分鐘來進行。接 著添加80 μΐ無抗生素且含有2·〇χ104 H441細胞之完全生長 培養基。細胞培育24小時，隨後RNA純化。在0.1或10 ηΜ 最終雙鏈體濃度下進行實驗，使用55個β-ENaC雙鏈體中每 154740.doc • 162- 201141489 一者單次劑量篩選。各siRNA在各測試劑量下轉染3次。結 果顯示於表3中。 在10 nM至10 fM濃度範圍上使用連續稀釋液來檢定在10 nM及0.1 nM篩選中顯示穩固沉默之雙鏈體子組以測定其 IC50。結果顯示於表4中。 總RNA分離： 採集細胞且溶解於140 μΐ溶解/結合溶液中，接著在850 rpm下使用Eppendorf Thermomixer(整個過程中混合速度相 同）混合1分鐘。 使用 MagMAX-96 總 RNA 分離套組（Applied Biosystem， Foster City CA，part #: AMI 830)分離總 RNA。將 20 μΐ磁珠 及溶解/結合增強劑混合物添加至細胞溶解產物中且混合5 分鐘。使用磁性台架捕捉磁珠且移除上清液而不擾亂珠 粒。移除上清液後，磁珠以洗滌溶液1 (添加之異丙醇）洗滌 且混合1分鐘。再次捕捉珠粒且移除上清液。珠粒接著以 150 μΐ洗滌溶液2(添加之乙醇）洗滌，捕捉且移除上清液。 接著將50 μΐ DNase混合物（MagMax turbo DNase緩衝液及 Turbo DNase)添加至珠粒中且將其混合10至15分鐘。混合 後，添加100 μΐ RNA再結合溶液且混合3分鐘。移除上清 液且磁珠以150 μΐ洗滌溶液2再次洗滌且混合1分鐘，且完 全移除上清液。磁珠混合2分鐘直至乾燥，隨後RNA以50 μΐ水溶離。 cDNA合成： ABI大容量 cDNA反轉錄套組（Applied Biosystems，Foster 154740.doc -163- 201141489• The synthesis of the above sequences was carried out in a 96-well plate on a 1 μηι scale. The amidite solution was prepared at a concentration of 〇M, and ethylthiotetrazole (6 M in acetonitrile) was used as an activator. The synthesized sequence was cleaved in a 96-well plate and the protecting group was removed, the indoleamine was used in the first step and the fluoride reagent was used in the second step. The crude sequence was made using a mixture of propylene steel and ethanol (80.20) and the pellet was resuspended in 〇2 μ sodium acetate buffer. Samples from each sequence were analyzed by LC-MS to confirm identity&apos; UV quantification and the selected sample set was determined by chromatography. Purification and Desalting: 154740.doc -161 - 201141489 Purification of the β-ENaC sequence using a Source 15Q column on an AKTA explorer purification system. A column temperature of 65 ° C was maintained during the purification. Sample injection and collection were performed in 96-well (1.8 mL deep well) plates. A single peak corresponding to the full length sequence in the eluent was collected. The purified sequence was desalted on a Sephadex G25 column using an AKTA purifier. The concentration of the desalted β-ENaC sequence (measured by UV at A260) and purity (by ion exchange HPLC) were analyzed. The individual strands are then bonded. A detailed list of β-ENaC single and duplexes is shown in Table 1 above. The duplex was used for in vitro screening to test its ability to block the beta-ENaC gene content. Example 3. In Vitro Screening of P-ENaC RNAi Agents β-ENaC RNAi agents were screened in vitro to determine their ability to block the β-ENaC gene content. Cell culture and transfection: H441 (ATCC, Manassas, VA) cells were supplemented with 10% FBS, streptomycin and novolac (ATCC) at 37 ° C in a 5% C〇2 atmosphere. RPMI 1640 (ATCC) was grown to near confluence and subsequently released from the plate by trypsin treatment. Reverse staining was performed by adding 5 μΐ Opti-MEM to each well of 10 μΐ Opti-MEM plus 0.2 μL of lipofectamine RNAiMax (Invitrogen, Carlsbad CA. Cat. No. 13778-150) to 5 μM per well in a 96-well plate. The siRNA duplex was applied and incubated for 15 minutes at room temperature. Then, 80 μl of a complete growth medium containing no antibiotics and containing 2·〇χ104 H441 cells was added. The cells were incubated for 24 hours followed by RNA purification. Experiments were performed at a final duplex concentration of 0.1 or 10 ηΜ using a single dose screening of 154740.doc • 162- 201141489 in 55 β-ENaC duplexes. Each siRNA was transfected 3 times at each test dose. The results are shown in Table 3. Serial dilutions were used on a concentration range of 10 nM to 10 fM to characterize a subset of duplexes showing robust silencing in 10 nM and 0.1 nM screens to determine their IC50. The results are shown in Table 4. Total RNA isolation: Cells were harvested and dissolved in 140 μM dissolution/binding solution, followed by mixing at 850 rpm for 1 minute using an Eppendorf Thermomixer (mixing speed throughout the process). Total RNA was isolated using the MagMAX-96 Total RNA Isolation Kit (Applied Biosystem, Foster City CA, part #: AMI 830). 20 μM magnetic beads and a dissolution/binding enhancer mixture were added to the cell lysate and mixed for 5 minutes. Use a magnetic gantry to capture the beads and remove the supernatant without disturbing the beads. After removing the supernatant, the magnetic beads were washed with Wash Solution 1 (added isopropanol) and mixed for 1 minute. The beads were again captured and the supernatant removed. The beads were then washed with 150 μΐ Wash Solution 2 (added ethanol), and the supernatant was captured and removed. A 50 μΐ DNase mixture (MagMax turbo DNase buffer and Turbo DNase) was then added to the beads and mixed for 10 to 15 minutes. After mixing, 100 μM of RNA was added and the solution was combined and mixed for 3 minutes. The supernatant was removed and the magnetic beads were washed again with 150 μΐ of the washing solution 2 and mixed for 1 minute, and the supernatant was completely removed. The beads were mixed for 2 minutes until dry, after which the RNA was dissolved in 50 μL of water. cDNA Synthesis: ABI Large Capacity cDNA Reverse Transcription Set (Applied Biosystems, Foster 154740.doc -163- 201141489

City, CA,目錄號4368813)用於CDNA合成。每次反應將2 μΐ l〇x緩衝液、0.8 μΐ 25x dNTP、2 μΐ隨機引子、1 μΐ反轉錄 酶、1 μΐ RNase抑制劑及3.2 μΐ Η20之主要混合物添加至1〇 μΐ總RNA中。藉由以下步驟使用Bio-Rad C-1000或S-1000 熱循環機（Hercules, CA)產生 CDNA: 25°C 10 min，37°C 120 min，85°C 5 sec，4°C保持。 即時PCR : 將2 μΐ cDNA添加至含有0.5 μΐ GAPDH TaqMan探針 (Applied Biosystems·目錄號 4326317E)、0.5 μΐ β-ENaC TaqMan 探針（Applied Biosystems 目錄號Hs00165722_ml)及 5 μΐ Roche探針主要混合物（R0Che Cat # 04887301001)的主 要混合物中，LightCycler 480 384孔板（Roche目錄號 0472974001)中總共每孔 1〇 μ卜即時PCR^LightCycler 480 即時PCR機（R0che)中進行。各雙鏈體在兩次獨立轉染中測 試，且每次轉染一式兩份檢定。 使用法分析即時資料。各樣品根據gaPDH表現校 正且相對於以非靶向雙鏈體AD-1955轉染評定阻斷。使用 XLfit中之4參數擬合模型定義IC5〇。 結果顯示於下文中。表3顯示在0.1 nM或10 nM最終雙鍵 體濃度下進行之實驗結果，使用55個0_£]^化雙鏈體中每一 者單次劑量篩選。「剩餘訊息物分數」指示10 nm或0.1 nM 下的殘餘基因含量。因此’第二行中針對AD-20832-bl之 「〇.17」表示在1〇 nMi濃度下’存在17%殘餘基因含量或 83%表現阻斷。亦注意字尾「bl」指示「批次丨」。因此， 154740.doc 201141489 舉例而言，名稱「AD-20832-bl」之RNAi劑具有與命名為 「AD-20832」之RNAi劑相同之序列。 表 3. β-ENaC 之 10 nM 及 0·1 nM 阻斷City, CA, catalog number 4368813) for CDNA synthesis. The main mixture of 2 μΐ l〇x buffer, 0.8 μΐ 25× dNTP, 2 μΐ random primer, 1 μΐ reverse transcriptase, 1 μΐ RNase inhibitor and 3.2 μΐ 20 was added to 1 μ μ of total RNA per reaction. CDNA was generated using a Bio-Rad C-1000 or S-1000 thermal cycler (Hercules, CA) by the following procedure: 25 ° C for 10 min, 37 ° C for 120 min, 85 ° C for 5 sec, 4 ° C to maintain. Real-time PCR: 2 μΐ cDNA was added to a 0.5 μΐ GAPDH TaqMan probe (Applied Biosystems Catalog No. 4326317E), 0.5 μΐ β-ENaC TaqMan probe (Applied Biosystems Cat. No. Hs00165722_ml) and a 5 μΐ Roche probe main mixture (R0Che) Cat # 04887301001) The main mixture, LightCycler 480 384-well plate (Roche catalog number 04472974001) was performed in a total of 1 μl per well on a real PCR^LightCycler 480 Instant PCR machine (R0che). Each duplex was tested in two independent transfections and replicated in duplicate for each transfection. Use the method to analyze real-time data. Each sample was corrected for gaPDH performance and blocked against a non-targeted duplex AD-1955 transfection assay. IC5〇 was defined using a 4-parameter fit model in XLfit. The results are shown below. Table 3 shows the results of experiments performed at a final double bond concentration of 0.1 nM or 10 nM using a single dose screen for each of the 55 0-folded duplexes. The "Remaining Message Score" indicates the residual gene content at 10 nm or 0.1 nM. Therefore, "〇.17" for AD-20832-bl in the second row indicates that there is 17% residual gene content or 83% performance blockade at 1〇 nMi concentration. Also note that the suffix "bl" indicates "batch status". Thus, 154740.doc 201141489 For example, the RNAi agent of the name "AD-20832-bl" has the same sequence as the RNAi agent designated "AD-20832". Table 3. 10 nM and 0·1 nM blocking of β-ENaC

10 nM下之剩 餘訊息物分數 0.1 nM下之剩 餘訊息物分數 10 nM下之 標準差 0.1 nM下之標 準差 AD-20832-bl 0.17 0.33 0.04 0.03 AD-20848-bl 0.17 0.49 0.01 0.04 AD-20807-bl 0.18 0.26 0.02 0.05 AD-20826-bl 0.19 0.49 0.02 0.22 AD-20837-bl 0.19 0.51 0.04 0.04 AD-20861-bl 0.19 0.71 0.02 0.29 AD-20834-bl 0.20 0.34 0.06 0.05 AD-20806-bl 0.22 0.60 0.02 0.15 AD-20851-bl 0.23 0.55 0.04 0.07 AD-20865-bl 0.24 0.64 0.02 0.05 AD-20811-bl 0.25 0.52 0.17 0.23 AD-20819-bl 0.27 0.60 0.01 0.07 AD-20839-bl 0.27 0.55 0.06 0.05 AD-20835-bl 0.28 0.63 0.07 0.21 AD-20825-bl 0.30 0.72 0.11 0.15 AD-20867-bl 0.30 0.68 0.00 0.20 AD-20813-bl 0.34 0.56 0.17 0.36 AD-20823-bl 0.34 0.75 0.05 0.05 AD-20805-bl 0.36 0.86 0.02 0.09 AD-20831-bl 0.36 0.60 0.01 0.21 AD-20862-bl 0.38 0.93 0.02 0.29 AD-20808-bl 0.40 0.81 0.13 0.16 AD-20827-bl 0.40 2.55 0.07 1.44 AD-20828-bl 0.42 0.89 0.11 0.25 AD-20812-bl 0.47 0.74 0.32 0.36 AD-20836-bl 0.48 1.07 0.11 0.27 AD-20822-bl 0.49 0.94 0.11 0.09 AD-20810-bl 0.53 0.87 0.25 0.20 AD-20824-bl 0.54 1.12 0.08 0.33 AD-20844-bl 0.55 0.98 0.07 0.28 AD-20814-bl 0.60 1.30 0.09 0.12 AD-20838-bl 0.65 1.18 0.07 0.18 AD-20816-bl 0.66 1.38 0.05 0.17 AD-20845-bl 0.72 1.18 0.01 0.27 AD-20820-bl 0.75 0.89 0.06 0.14 AD-20830-bl 0.75 0.94 0.04 0.24 AD-20866-bl 0.77 1.24 0.03 0.57 AD-20809-bl 0.78 1.05 0.05 0.03 AD-20833-bl 0.79 0.99 0.01 0.35 AD-20821-bl 0.80 0.99 0.07 0.14 154740.doc •165· 201141489 AD-20846-bl 0.83 1.13 0.10 0.15 AD-20818-bl 0.88 1.36 0.04 0.62 AD-20817-bl 0.89 1.11 0.11 0.19 AD-20843-bl 0.92 1.64 0.11 0.16 AD-20840-bl 0.93 1.13 0.15 0.30 AD-20847-bl 0.94 0.99 0.64 0.12 AD-20815-bl 0.96 2.06 0.23 0.99 AD-20842-bl 0.96 1.37 0.16 0.28 AD-20852-bl 0.96 1.30 0.17 0.17 AD-20863-bl 0.99 0.84 0.24 0.11 AD-20864-bl 0.99 1.36 0.05 0.74 AD-20850-bl 1.00 1.22 0.14 0.14 AD-20829-bl 1.08 1.39 0.26 0.70 AD-20849-bl 1.11 1.31 0.27 0.17 AD-20841-bl 1.12 1.37 0.10 0.48 此等實驗中使用之針對β-ENaC之所有RNAi劑為表1中所 列之經修飾序列（SEQ ID NO: 1至110)。 表4顯示在10 nM至10 fM濃度範圍上使用連續稀釋液檢 定在10 nM及0.1 nM篩選中顯示穩固沉默之雙鏈體子組以 測定其IC50的實驗結果。 表4. β-ENaC劑量反應篩選 H441新(平均4次重複） H441舊(平均8次重複） 雙鏈體_ID IC50nM IC50標準差 IC50nM IC50標準差 AD-20807 0.05 0.03 0.04 0.06 AD-20826 0.14 0.05 0.05 0.07 AD-20832 0.05 0.02 0.04 0.05 AD-20834 0.06 0.03 0.03 0.06 AD-20848 0.25 0.14 0.13 0.17 AD-20861 0.13 0.08 0.09 0.06 實例4 β-ENaC RNAi 劑 AD-20807 及 AD-20832 之活趙内分析 在活體内實驗中，測試兩種β-ENaC RNAi劑AD-20807及 AD-20832在大鼠整個肺中阻斷β-ENaC基因含量的能力。 目的為測定劑量反應。亦量測免疫刺激。 所用之大鼠品系為史泊格多利（Sprague-Dawley);個體 154740.doc •166· 201141489 重量約280-300 g。大鼠每天給藥一次，持續2天。接著在 第二次給藥後約24小時’將其處死。取左肺且研磨用於 qPCR測定β-ENaC含量；右肺冷凍且儲存。 表5. 組 大鼠編號 調配物 濃度 每組之大鼠 1 1-5 D5W NA 5 2 6-10 AD1955 10mg/kg 5 3 11-15 AD20191 10mg/kg 5 4 16-20 AD20807 10mg/kg 5 5 12-25 AD20807 3mg/kg 5 6 26-30 AD20S07 1 mg/kg 5 7 31-35 AD20832 lOmg/kg 4* 8 36-40 AD20832 3mg/kg 5 9 41-45 AD20832 1 mg/kg 5Remaining message score at 10 nM Remaining message score at 0.1 nM Standard deviation at 10 nM Standard deviation at 0.1 nM AD-20832-bl 0.17 0.33 0.04 0.03 AD-20848-bl 0.17 0.49 0.01 0.04 AD-20807- Bl 0.18 0.26 0.02 0.05 AD-20826-bl 0.19 0.49 0.02 0.22 AD-20837-bl 0.19 0.51 0.04 0.04 AD-20861-bl 0.19 0.71 0.02 0.29 AD-20834-bl 0.20 0.34 0.06 0.05 AD-20806-bl 0.22 0.60 0.02 0.15 AD-20851-bl 0.23 0.55 0.04 0.07 AD-20865-bl 0.24 0.64 0.02 0.05 AD-20811-bl 0.25 0.52 0.17 0.23 AD-20819-bl 0.27 0.60 0.01 0.07 AD-20839-bl 0.27 0.55 0.06 0.05 AD-20835-bl 0.28 0.63 0.07 0.21 AD-20825-bl 0.30 0.72 0.11 0.15 AD-20867-bl 0.30 0.68 0.00 0.20 AD-20813-bl 0.34 0.56 0.17 0.36 AD-20823-bl 0.34 0.75 0.05 0.05 AD-20805-bl 0.36 0.86 0.02 0.09 AD -20831-bl 0.36 0.60 0.01 0.21 AD-20862-bl 0.38 0.93 0.02 0.29 AD-20808-bl 0.40 0.81 0.13 0.16 AD-20827-bl 0.40 2.55 0.07 1.44 AD-20828-bl 0.42 0.89 0.11 0.25 AD-20812-bl 0.47 0.74 0.32 0.36 AD-20836-bl 0.48 1.07 0.11 0.27 AD-20822-bl 0.49 0.94 0.11 0.09 AD-20810-bl 0.53 0.87 0.25 0.20 AD-20824-bl 0.54 1.12 0.08 0.33 AD-20844-bl 0.55 0.98 0.07 0.28 AD-20814-bl 0.60 1.30 0.09 0.12 AD-20838-bl 0.65 1.18 0.07 0.18 AD-20816- Bl 0.66 1.38 0.05 0.17 AD-20845-bl 0.72 1.18 0.01 0.27 AD-20820-bl 0.75 0.89 0.06 0.14 AD-20830-bl 0.75 0.94 0.04 0.24 AD-20866-bl 0.77 1.24 0.03 0.57 AD-20809-bl 0.78 1.05 0.05 0.03 AD-20833-bl 0.79 0.99 0.01 0.35 AD-20821-bl 0.80 0.99 0.07 0.14 154740.doc •165· 201141489 AD-20846-bl 0.83 1.13 0.10 0.15 AD-20818-bl 0.88 1.36 0.04 0.62 AD-20817-bl 0.89 1.11 0.11 0.19 AD-20843-bl 0.92 1.64 0.11 0.16 AD-20840-bl 0.93 1.13 0.15 0.30 AD-20847-bl 0.94 0.99 0.64 0.12 AD-20815-bl 0.96 2.06 0.23 0.99 AD-20842-bl 0.96 1.37 0.16 0.28 AD-20852 -bl 0.96 1.30 0.17 0.17 AD-20863-bl 0.99 0.84 0.24 0.11 AD-20864-bl 0.99 1.36 0.05 0.74 AD-20850-bl 1.00 1.22 0.14 0.14 AD-20829-bl 1.08 1.39 0.26 0.70 AD-20849-bl 1.11 1.31 0.27 0.17 AD-20841-bl 1.12 1.37 0.10 0.48 used in these experiments for β-ENaC RNAi agent is a modified sequence (SEQ ID NO: 1 to 110) columns of Table 1. Table 4 shows the results of an assay to determine the IC50 of a stable subset of duplexes showing stable silencing in 10 nM and 0.1 nM screens using serial dilutions over a concentration range of 10 nM to 10 fM. Table 4. β-ENaC dose response screening H441 new (average 4 replicates) H441 old (average 8 replicates) duplex _ID IC50nM IC50 standard deviation IC50nM IC50 standard deviation AD-20807 0.05 0.03 0.04 0.06 AD-20826 0.14 0.05 0.05 0.07 AD-20832 0.05 0.02 0.04 0.05 AD-20834 0.06 0.03 0.03 0.06 AD-20848 0.25 0.14 0.13 0.17 AD-20861 0.13 0.08 0.09 0.06 Example 4 β-ENaC RNAi Agents AD-20807 and AD-20832 In vivo, the ability of two β-ENaC RNAi agents AD-20807 and AD-20832 to block the β-ENaC gene content in the entire lung of the rat was tested. The purpose is to determine the dose response. Immunostimulation is also measured. The rat strain used was Sprague-Dawley; the individual 154740.doc •166· 201141489 weighed approximately 280-300 g. Rats were dosed once daily for 2 days. It was then sacrificed about 24 hours after the second dose. The left lung was taken and ground for qPCR determination of β-ENaC content; the right lung was frozen and stored. Table 5. Group Rat No. Formulation Concentration Rats in each group 1 1-5 D5W NA 5 2 6-10 AD1955 10 mg/kg 5 3 11-15 AD20191 10 mg/kg 5 4 16-20 AD20807 10 mg/kg 5 5 12-25 AD20807 3mg/kg 5 6 26-30 AD20S07 1 mg/kg 5 7 31-35 AD20832 lOmg/kg 4* 8 36-40 AD20832 3mg/kg 5 9 41-45 AD20832 1 mg/kg 5

，在4隻的組中，5隻大鼠初始給藥，但各組中有1隻未在 實驗中生還且不包括於最終資料中。 兩種針對β-ENaC之RNAi劑（AD20807及AD20832)顯示卜 ENaC含量以劑量依賴性方式降低。對於AD20807，β_ ENaC之含量在1、3及10 mg/kg劑量下分別降低約30〇/〇、 40%及 50% » 相反，P_ENaC(bENaC)RNAi劑不會降低a_ENaC(aENaC) 之含量。然而，投與AD20832使α-ENaC增加。 陰性對照包括： D5W : 5°/。右旋糖於水中之溶液；其為給藥時用於稀釋 siRNA之媒劑；AD1955 :不特異性乾向a_4p_ENaC，但把 向螢火蟲螢光素酶之siRNA ;及AD20191 :不結合於β-ENaC，但輕向大鼠α-ENaC之siRNA ;及AD-9201，其把向 a-ENaC(未用於此特定實例中）。 154740.doc -167- 201141489 因此，此實驗中用RNAi劑AD20807及AD20832可見特異 性阻斷β-ENaC。 實例5 活體内分析P-ENaC AD-20834 在活體内實驗中，測試β-ENaC RNAi劑AD20834在大鼠 整個肺中阻斷β-ENaC基因含量的能力。目的為測定劑量反 應。亦量測免疫刺激。 大鼠品系為史泊格多利；個體重量約280-300 g。大鼠每 天給藥一次’持續2天。接著在第二次給藥後約24小時， 將其處死。取左肺且研磨用於qPCR測定β-ENaC含量；右 肺冷凍且儲存。 表6. 組 大鼠編號 調配物 濃度 每組大鼠 1 1-5 D5W NA 5 2 6-10 AD1955 10mg/kg 41 3 11-15 AD20191 10mg/kg 5 4 16-20 AD20834 10mg/kg 5 5 21-25 AD20834 3mg/kg 5 6 26-30 AD20834 lmg/kg 41 154740.doc • 168 · 1 在4隻的組中，5隻大鼠初始給藥，但各組中有1隻未在 實驗中生還且不包括於最終資料中。 假定重量為300 g(0.3 kg)，進行以下稀釋： 10 mg/kg=200 μι體積中 3 mg siRNA=15 mg/mL 3 mg/kg=200 pL體積中 1 mg siRNA=5 mg/mL 1 mg/kg=200 μ；ί體積中 0.3 mg siRNA=1.5 mg/mL 資料根據PPIB [肽基-輔胺醯基順-反異構酶B，用作管家 (校正）基因]校正。 201141489 實驗顯示，在史泊格多利大鼠中，β-ENaC RNAi劑 AD20834證明β-ENaC含量減少約40%。此作用對β-EnaC具 有特異性》 對照組如下：D5W(含5%右旋糖之水）為陰性對照，對(X-ENaC或β-ENaC含量不顯示作用。AD1955為不結合於α-或 β-ENaC之對照siRNA，其對α-或β-ENaC含量亦顯示幾乎無 作用。靶向ct-ENaC但不靶向β-ENaC之陽性對照siRNA φ AD20191證明α-ENaC含量，但非β-ENaC含量減少約50%。 因此，10 mg/kg的劑量之β-ENaC RNAi劑AD20834證明 至少約40%抑制史泊格多利大鼠中β-ENaC基因表現》 實例6 分析 β-ENaC RNAi劑 使用 β-ENaC RNAi 劑 AD20807、AD20832、AD20834、 AD20848及AD20861在史泊格多利大鼠中活體内進行其他 實驗。在第1天及第2天，大鼠以10 mg/kg D5W給藥，且在 # 第3天處死，且收集肺。 結果顯示於圖1中。結果顯示來自左肺之qPCR資料，根 據對照基因PPIB校正。 圖1中之對照組如下：D5W(含5%右旋糖之水）為陰性對 照，對α-ENaC或β-ENaC含量不顯示作用。陽性對照為AD-9201，其靶向 a-ENaC(aENaC)。 結杲顯示於圖1中，顯示AD20807、AD20832、 AD20834、AD20848及AD20861統計學上顯著且特異性阻 斷P-ENaC(bENaC)。史泊格多利大鼠中的β-ENaC基因之表 154740.doc -169· 201141489 現由10 mg/kg濃度之此等RNAi劑抑制至少約40%。 實例7 人類支氣管上皮細胞中P-ENaC RNAi劑AD20832對ENaC 通道功能活性之活體外作用 人類支氣管上皮細胞（HBEC)以指示之siRNA(包括β-ENaC RNAi劑AD20832)轉染。經轉染細胞接種至Snapwell ***物中且培養24小時。隨後，自各***物移除頂部培養 基且細胞在氣液界面（ALI)培養。在所述之ALI後第8天， 檢定細胞之ENaC及CFTR活性。為了控制細胞活力，根據 CFTR活性校正ENaC功能且資料以相對於未經轉染對照組 的百分比形式給出（圖2 A) »亦量測跨膜電阻作為其他活力 對照（圖2B)。對各***物進行α及β ENaC子單元mRNA之 表現分析且根據GAPDH表現校正。（圖2C)。資料表明7〇% 抑制mRNA表現足以50%功能抑制ENaC通道。對於阻斷α 或β子單元皆如此，其中每一者皆與未經轉染（neg)及非特 異性（ns)siRNA對照組比較。資料亦顯示β ENaC siRNA不 會抑制a ENaC mRNA表現且反之亦然。 方法：人類支氣管上皮細胞中之ENaC功能活性 人類支氣管上皮細胞（HBEC)購自Lonza且在生長培養基 (BEGM加singlequots-Lonza)中冷凍之前繼代一次。隨後’ 解凍細胞，擴增至匯合且1:10倍裂解用於轉染°達到80% 匯合後，各燒瓶之細胞以使用含2 gL/rnL脂染胺2〇〇〇之總 體積30 mL的轉染培養基（BEGM(Lonza)與卩^^厘高葡萄糖 (Gibco)的1:1混合物，無添加劑）以30 nM指示之siRNA轉 154740.doc -170· 201141489Of the 4 groups, 5 rats were initially administered, but 1 of each group was not survived in the experiment and was not included in the final data. Two RNAi agents (AD20807 and AD20832) against β-ENaC showed a decrease in the content of ENaC in a dose-dependent manner. For AD20807, the content of β_ENaC was reduced by about 30〇/〇, 40%, and 50% at doses of 1, 3, and 10 mg/kg, respectively. In contrast, P_ENaC(bENaC)RNAi did not reduce the amount of a_ENaC (aENaC). However, administration of AD20832 increased alpha-ENaC. Negative controls included: D5W: 5°/. a solution of dextrose in water; it is a vehicle for diluting siRNA when administered; AD1955: siRNA that does not specifically dry to a_4p_ENaC, but to firefly luciferase; and AD20191: does not bind to β-ENaC But lightly directed to rat α-ENaC siRNA; and AD-9201, which is directed to a-ENaC (not used in this particular example). 154740.doc -167- 201141489 Therefore, the RNAi agents AD20807 and AD20832 were used to specifically block β-ENaC in this experiment. Example 5 In vivo analysis of P-ENaC AD-20834 In vivo, the ability of the β-ENaC RNAi agent AD20834 to block the β-ENaC gene content in the entire lung of the rat was tested. The purpose is to determine the dose response. Immunostimulation is also measured. The rat strain is Spoeldoly; the individual weighs approximately 280-300 g. Rats were dosed once a day for 2 days. It was then sacrificed about 24 hours after the second administration. The left lung was taken and ground for qPCR determination of β-ENaC content; the right lung was frozen and stored. Table 6. Group Rat No. Formulation Concentrations 1 1-5 D5W NA 5 2 6-10 AD1955 10 mg/kg 41 3 11-15 AD20191 10 mg/kg 5 4 16-20 AD20834 10 mg/kg 5 5 21 -25 AD20834 3mg/kg 5 6 26-30 AD20834 lmg/kg 41 154740.doc • 168 · 1 Of the 4 groups, 5 rats were initially administered, but 1 in each group was not survived in the experiment. It is not included in the final data. Assuming a weight of 300 g (0.3 kg), the following dilutions are made: 3 mg siRNA = 15 mg/mL 3 mg/kg = 200 pL volume 1 mg siRNA = 5 mg/mL 1 mg in a volume of 10 mg/kg = 200 μιη /kg=200 μ; ί 0.3 mg siRNA = 1.5 mg/mL in the volume was corrected according to PPIB [peptidyl-co-aminopurine cis-trans isomerase B, used as a housekeeping (correction) gene]. The 201141489 experiment showed that in the Spogdogi rats, the β-ENaC RNAi agent AD20834 proved a β-ENaC content reduction of about 40%. This effect is specific for β-EnaC. The control group is as follows: D5W (water containing 5% dextrose) is a negative control, and does not show effects on X-ENaC or β-ENaC content. AD1955 is not bound to α- Or β-ENaC control siRNA, which showed almost no effect on α- or β-ENaC content. Positive control siRNA φ AD20191 targeting ct-ENaC but not targeting β-ENaC proved α-ENaC content, but non-β - ENaC content is reduced by about 50%. Therefore, the 10 mg/kg dose of β-ENaC RNAi agent AD20834 demonstrates that at least about 40% inhibits the expression of β-ENaC gene in S. striata rats. Example 6 Analysis of β-ENaC RNAi Other experiments were performed in vivo in S. gerolid rats using β-ENaC RNAi agents AD20807, AD20832, AD20834, AD20848 and AD20861. On days 1 and 2, rats were dosed at 10 mg/kg D5W, and The rats were sacrificed on day 3 and the lungs were collected. The results are shown in Figure 1. The results show qPCR data from the left lung, corrected according to the control gene PPIB. The control group in Figure 1 is as follows: D5W (containing 5% dextrose) Water) was a negative control and showed no effect on α-ENaC or β-ENaC content. The positive control was AD-9201, which was targeted. a-ENaC (aENaC). The crusting is shown in Figure 1 and shows that AD20807, AD20832, AD20834, AD20848, and AD20861 are statistically significant and specifically block P-ENaC (bENaC). Beta in Shipodogoli rats -ENaC gene table 154740.doc -169· 201141489 is now inhibited by at least about 40% of these RNAi agents at a concentration of 10 mg/kg. Example 7 P-ENaC RNAi agent in human bronchial epithelial cells AD20832 is functionally active against ENaC channels Exogenous human bronchial epithelial cells (HBEC) were transfected with the indicated siRNA (including the β-ENaC RNAi agent AD20832). Transfected cells were seeded into Snapwell inserts and cultured for 24 hours. Subsequently, the top medium was removed from each insert and The cells were cultured at the gas-liquid interface (ALI). The cells were assayed for ENaC and CFTR activity on day 8 after ALI. To control cell viability, ENaC function was corrected for CFTR activity and data were compared to untransfected controls. The percentage is given as a percentage (Fig. 2A). The transmembrane resistance is also measured as a further viability control (Fig. 2B). The performance of the alpha and beta ENaC subunit mRNAs is analyzed for each insert and corrected for GAPDH performance (Fig. 2C). ).data Ming 7〇% 50% inhibition of mRNA expression is sufficient to inhibit the ENaC channel function. This was true for blocking alpha or beta subunits, each of which was compared to untransfected (neg) and non-specific (ns) siRNA controls. The data also show that β ENaC siRNA does not inhibit a ENaC mRNA expression and vice versa. Method: ENaC functional activity in human bronchial epithelial cells Human bronchial epithelial cells (HBEC) were purchased from Lonza and subcultured once in growth medium (BEGM plus singlequots-Lonza). Subsequently 'thawed cells, expanded to confluence and 1:10-fold lysis for transfection. After reaching 80% confluence, the cells of each flask were used with a total volume of 30 mL containing 2 g of L/rnL of amine. Transfection medium (1:1 mixture of BEGM (Lonza) and 卩^^g high glucose (Gibco), no additives) siRNA indicated by 30 nM to 154740.doc -170· 201141489

染。轉染後24小時，以分化培養基（BEBM與具有 singlequots之DMEM/高葡萄糖之50:50混合物（減去三块蘇 胺酸及視黃酸補充物，所有反式視黃酸單獨在50 nM下添 加））中2.5&gt;&lt;105個細胞/***物將細胞接種至6孔81^口评611插 入物（Costar)上。細胞頂部補充0.5 mL分化培養基及基側 補充2.5 mL分化培養基。在***物上再培養24小時後，置 換基側培養基且移除頂部培養基，因此使細胞進行氣液界 面（ALI)培養。在ALI後第8天（D8)，檢定細胞之ENaC及 CFTR活性。 為了評定經轉染細胞之離子傳輸表型，將Snapwell*** 物安置於垂直擴散室（Costar)中且以保持於37°C下含有（以 mM為單位）：120 NaCl、25 NaHC03、3·3 KH2P〇4、0.8 K2HP〇4、1·2 CaCl2、1.2 MgCl2及10葡萄糖（容積滲透濃度 保持介於280與300 mosmol/1之間）之氣封林格氏溶液 (gassed Ringer solution)(含 5% C〇2之 〇2; pH 7.4)連續浸 洗。細胞電壓箝制至〇 mV(EVC4〇00型；WPI)。藉由以30 s間隔施加2 mV脈衝且使用歐姆定律（Ohm's law)計算跨膜 電阻（TM res)來量測TM res。使用PowerLab工作站（ADI Instruments)記錄短路電流資料。藉由頂部添加10 μΜ ENaC阻斷劑阿米洛利（阿米洛利敏感性電流）後之短路電流 變化評定各組中ENaC通道之活性。藉由頂部及基側添加 0.6 μΜ已知活化CFTR之弗斯可林（Forskolin)(弗斯可林反 應）後短路電流的變化評定經CFTR之氯化物分泌。對於各 ***物，根據弗斯可林反應校正阿米洛利敏感電流且資料 154740.doc -171 - 201141489 以相對於未經轉染對照組之百分比形式給出。在研究結束 時，溶解各***物用於RNA分析（300 μι RLT緩衝液-Qiagen)，且保留樣品用於隨後分析所述rtPCR之mRNA阻 斷。 縮寫： ALI 氣液界面 BEGM 支氣管上皮生長培養基 D6、D8 第6天、第8天 DMEM 杜爾貝科改良之伊格爾培養基（Dulbecco's Modified Eagle Medium) HBEC 人類支氣管上皮細胞 TM res 跨膜電阻 等效物 一種包含RNAi劑之組合物，該RNAi劑包含有義股及反 義股，其中該反義股包含有〇、1、2或3個核苷酸與對表1 中提供之β-EnaC具有特異性之RNAi劑之反義股不同的至 少15個連續核苷酸。 如段落[00879]之組合物，其中該組合物另外包含針對β-ENaC之第二 RNAi 劑。 如段落[00879]之組合物，其中反義股之長度為30或30 個以下核苷酸。 如段落[00879]之組合物，其中有義股與反義股形成長 度為15至30個核苷酸對之雙鏈體區。 如段落[00879]之組合物，其中反義股及有義股之長度 154740.doc •172· 201141489 獨立為19至23個核皆酸。 如段落[00879]之組合物’其中RNAi劑包含使RNAi劑在 生物樣品或環境中穩定性提高的修飾。 如段落[00879]之組合物，其中RNAi劑包含至少一個經 修飾骨架及/或至少一個2'-經修飾核苷酸。 如段落[00879]之組合物，其中RNAi劑包含： a) 至少一個5'-尿苷-腺嘌呤_3’(5'-ua-3，）二核苷酸，其中 尿苷為2'·經修飾之核苷酸；及/或 b) 至少一個5，-尿苷·鳥嘌呤_3，（5'-ug·3')二核苷酸，其中 5'-尿皆為2'-經修飾之核苷酸；及/或 c) 至少一個5’-胞苷-腺嘌呤·3'(5'-ε3-3')二核苷酸，其中 5'-胞苷為2、經修飾之核苷酸；及/或 d) 至少一個5’-尿苷尿苷_3'(5，-uu-3，）二核苷酸，其中5'-尿苷為2’-經修飾之核苷酸。 如段落[00879]之組合物，其中RNAi劑包含選自由以下 組成之群的2，-修飾：2，-去氧、2，-去氧-2，-氟、2，-0-曱基、 2’-0-甲氧基乙基（2，-〇·μ〇Ε)、2，-0-胺基丙基（2.-0-AP)、 2'-0-二甲胺基乙基（2'-〇-DMAOE)、2，-0-二甲胺基丙基（2，-O-DMAP)、2’-〇-二曱胺基乙氧基乙基（2'-〇-DMAEOE)及 2’-〇-N-曱基乙醯胺基（2·-〇-ΝΜΑ)。 如段落[00879]之組合物，其中RNAi劑包含鈍端。 如段落[00879]之組合物，其中RNAi劑包含具有1至4未 配對核苷酸之懸垂物。 如段落[00879]之組合物，其中RNAi劑在RNAi劑之反義 154740.doc -173· 201141489 版的3’ -端包含懸垂物。 如段落[00879]之組合物，其中該尺舰劑接合至一或多 種選自以下之藥劑：診斷化合物、報導基團、交聯劑、賦 予核酸酶抗性之部分、天然或非尋常核苷鹼基、親脂性分 子、膽固醇、脂質、植物凝集素、類固醇、烏蘇醇、龍舌 蘭息苦元、薯蕷皂普元、㈣、三莊、藉葜息苦元、無羈 萜、表木栓醇衍生之石膽酸、維生素、碳水化合物、聚葡 萄糖、普魯蘭、甲殼素、聚葡萄胺糖、合成碳水化合物、 寡乳酸酯15-聚合體、天然聚合物、低分子量或中等分子 量聚合物、菊糖、環糊精、玻尿酸、蛋白質、蛋白質結合 齊J乾向整合素之分子、聚陽離子、肽、多元胺、肽模擬 物及/或運鐵蛋白。 如段落[00879]之組合物，其中RNAi劑在H441細胞中在 1〇 nM之濃度下能夠將P-ENaC基因之表現活體外抑制至少 約 60%。 如段落[00879]之組合物，其中RNAi劑在H441細胞中在 1〇 nM之濃度下能夠將β-ENaC基因之表現活體外抑制至少 約 70%。 如段落[00879]之組合物，其中RNAi劑在H441細胞中在 1 〇 nM之濃度下能夠將β—ENaC基因之表現活體外抑制至少 約 8 0 %。 如段落[00879]之組合物，其中RNAi劑在H441細胞中在 10 nM之濃度下能夠將β—ENaC基因之表現活體外抑制至少 約 90%。 154740.doc -174- 201141489 如段落[00879]之組合物，其中RNAi具有不超過約0.1 nM之 EC50。 如段落[00879]之組合物，其中RNAi具有不超過約0.01 nM之EC50。 如段落[00879]之組合物，其中RNAi具有不超過約0.001 nM之EC50。 一種包含RNAi劑之組合物，該RNAi劑包含第一股及第 二股，其中該第一股及該第二股包含分別有0、1、2或3個 核苷酸與對表1中提供之β-EnaC具有特異性之RNAi劑之第 一股及第二股不同的至少15個連續核苷酸。 如段落[00899]之組合物，其中該組合物包含針對β-ENaC之第二 RNAi 劑。 如段落[00899]之組合物，其中第二股之長度為30或30 個以下核苷酸。 如段落[00899]之組合物，其中第一股與第二股形成長 度為15至30個核苷酸對之雙鏈體區。 如段落[00899]之組合物，其中第一股及第二股之長度 獨立為19至23個核苷酸。 如段落[00899]之組合物，其中RNAi劑包含使RNAi劑在 生物樣品或環境中穩定性提高的修飾。 如段落[00899]之組合物，其中該RNAi劑包含硫代磷酸 酯及/或2'-經修飾核苷酸。 如段落[00899]之組合物，其中RNAi劑包含： 至少一個5’-尿苷-腺嘌呤-3’（5'-ua-3·)二核苷酸，其中尿 154740.doc -175- 201141489 苷為2’-經修飾之核苦酸；及/或至少一個5,_尿苷_鳥嘌呤_ 3 (5 -ug-3·)二核苷酸，其中5'-尿皆為2'-經修飾之核苷酸； 及/或至少一個5’-胞苷.腺嘌二核苷酸，其 中5'-胞苦為2'-經修飾之核苷酸； 及/或至少一個5’-尿苷.尿苷_3，(5，_uu_3i)二核苷酸，其中 5'-尿苷為2’-經修飾之核苷酸。 如段落[00899]之組合物，其中RNAi劑包含一或多個選 自由以下組成之群的2，-修飾： 2 -去氧、2’-去氧-2’-氟、2'-〇-曱基、2，-0-曱氧基乙基 (2 -O-MOE)、2’-〇-胺基丙基（2，_〇_Ap)、2，_〇_ 二甲胺基乙 基（2’-0-DMA0E)、2，-〇-二甲胺基丙基（2，_〇_DMAp)、2，·〇_ 二甲胺基乙氧基乙基（2·-〇·〇ΜΑΕΟΕ)及2，-〇-Ν-曱基乙醯胺 基（2·-〇-ΝΜΑ)。 如段落[00899]之組合物，其tRNAi劑包含鈍端。 如段落[00899]之組合物，其中RNAi劑包含具有1至4未 配對核苷酸之懸垂物。 如段落[00899]之組合物，其中RNAi劑在反義股的3，·端 包含懸垂物。 如段落[00899]之組合物，其中該RNAj^i接合至一或多 種藥劑，s亥藥劑選自以下：診斷化合物、報導基團、交聯 劑、賦予核酸酶抗性之部分、天然或非尋常核苷鹼基、親 脂性分子、膽固醇、脂質、植物凝集素、類固醇、烏蘇 醇、龍舌蘭皂苷元、薯蕷皂苷元、萜類、三萜、菝葜皂苷 元、無羁IS、表木检醇衍生之石膽酸、維生素、碳水化合 154740.doc •176· 201141489 物、聚葡萄糖、普魯蘭、曱殼素、聚葡萄胺糖、合成碳水 化合物、寡乳酸酯15-聚合體、天然聚合物、低分子量或 中等分子量聚合物、菊糖、環糊精、玻尿酸、蛋白質、蛋 白質結合劑、靶向整合素之分子、聚陽離子、肽、多元 胺、肽模擬物及/或運鐵蛋白。 如段落[00899]之組合物，其中RNAi劑在H441細胞中在 1 0 nM之濃度下能夠將β-ENaC基因之表現活體外抑制至少 約 60%。 如段落[00899]之組合物，其中RNAi劑在H441細胞中在 1 0 nM之濃度下能夠將β-ENaC基因之表現活體外抑制至少 約 70%。 如段落[00899]之組合物，其中RNAi劑在H441細胞中在 1 0 nM之濃度下能夠將β-ENaC基因之表現活體外抑制至少 約 80%。 如段落[00899]之組合物，其中RNAi劑在H441細胞中在 1 0 nM之濃度下能夠將β-ENaC基因之表現活體外抑制至少 約 90%。 如段落[00899]之組合物，其中RNAi具有不超過約0.1 nM之 EC50 〇 如段落[00899]之組合物，其中RNAi具有不超過約0.01 nM之EC50。 如段落[00899]之組合物，其中RNAi具有不超過約0.001 nM之 EC50。 一種治療個體之β-ENaC相關疾病之方法，其包含以下 154740.doc -177- 201141489 步驟：向個體投與治療有效量之包含RNAi劑之組合物， 該RNAi劑包含有義股及反義股，其中反義股包含有〇、 1、2或3個核苷酸與對表1中提供之β-ENaC具有特異性之 RNAi劑之反義股不同的至少15個連續核苷酸。 如段落[00919]之方法，其中該j3_ENaC相關疾病為囊腫 性纖維化、1型假醛固酮過少症（PHA1)、李德爾症候群、 高血壓、鹼中毒、低鉀血症及/或肥胖相關之高血壓。 如段落[00919]之方法，其中p_ENaC相關疾病為囊腫性 纖維化。 如段落[00919]之方法，其中該方法另外包含投與用於 囊腫性纖維化、1型假醛固酮過少症（PHA丨）、李德爾症候 群、尚血壓、驗中毒、低卸血症及/或肥胖相關之高血壓 之其他治療的步驟。 如段落[〇〇919]之方法，其中該組合物包含針對!3_ENaC 之第二RNAi劑。 如段落[〇〇919]之方法，苴117^? +、上dye. 24 hours after transfection, a differentiation medium (BEBM with a 50:50 mixture of DMEM/high glucose with singlequots (minus three pieces of threonine and retinoic acid supplements, all trans retinoic acid at 50 nM alone) Add)) 2.5 &gt;&lt; 105 cells/inserts The cells were seeded onto 6 well 81 口 611 inserts (Costar). The top of the cell was supplemented with 0.5 mL of differentiation medium and the basal side was supplemented with 2.5 mL of differentiation medium. After further incubation for 24 hours on the insert, the basal medium was replaced and the top medium was removed, thus allowing the cells to be cultured in a gas-liquid interface (ALI). On day 8 (D8) after ALI, the cells were assayed for ENaC and CFTR activity. To assess the ion transport phenotype of transfected cells, the Snapwell insert was placed in a vertical diffusion chamber (Costar) and contained at 37 ° C (in mM): 120 NaCl, 25 NaHC03, 3·3 Gassed Ringer solution (containing 5) of KH2P〇4, 0.8 K2HP〇4, 1·2 CaCl2, 1.2 MgCl2 and 10 glucose (with a volumetric osmotic concentration between 280 and 300 mosmol/1) 〇2 of % C〇2; pH 7.4) continuous dipping. The cell voltage was clamped to 〇 mV (EVC4〇00 type; WPI). TM res was measured by applying a 2 mV pulse at 30 s intervals and calculating the transmembrane resistance (TM res) using Ohm's law. Record short-circuit current data using a PowerLab workstation (ADI Instruments). The activity of the ENaC channel in each group was assessed by short-circuit current changes after the addition of 10 μΜ ENaC blocker amiloride (amiloride-sensitive current). The chloride secretion by CFTR was assessed by the addition of 0.6 μΜ of Forskolin (Forskolin reaction) with known activated CFTR on the top and basal side. For each insert, the amiloride-sensitive current was corrected according to the Forskolin reaction and the data 154740.doc -171 - 201141489 was given as a percentage relative to the untransfected control group. At the end of the study, each insert was lysed for RNA analysis (300 μL RLT buffer-Qiagen) and the sample was retained for subsequent analysis of the mRNA block of the rtPCR. Abbreviations: ALI gas-liquid interface BEGM bronchial epithelial growth medium D6, D8 Day 6 and Day 8 DMEM Dulbecco's Modified Eagle Medium HBEC Human bronchial epithelial cells TM res Transmembrane resistance equivalent A composition comprising a RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises 〇, 1, 2 or 3 nucleotides and has the β-EnaC provided in Table 1 The antisense strand of the specific RNAi agent differs by at least 15 contiguous nucleotides. The composition of paragraph [00879], wherein the composition further comprises a second RNAi agent for β-ENaC. The composition of paragraph [00879] wherein the antisense strand is 30 or less nucleotides in length. The composition of paragraph [00879] wherein the sense strand and the antisense strand form a duplex region of between 15 and 30 nucleotide pairs in length. The composition of paragraph [00879], wherein the length of the antisense and sense shares is 154740.doc • 172. 201141489 is independently 19 to 23 nucleotides. The composition of paragraph [00879] wherein the RNAi agent comprises a modification that increases the stability of the RNAi agent in a biological sample or environment. The composition of paragraph [00879] wherein the RNAi agent comprises at least one modified backbone and/or at least one 2'-modified nucleotide. The composition of paragraph [00879], wherein the RNAi agent comprises: a) at least one 5'-uridine-adenine_3' (5'-ua-3,) dinucleotide, wherein the uridine is 2'. Modified nucleotide; and/or b) at least one 5,-uridine-guanine_3, (5'-ug·3') dinucleotide, wherein 5'-urine is 2'- Modified nucleotide; and/or c) at least one 5'-cytidine-adenine 3' (5'-ε3-3') dinucleotide, wherein 5'-cytidine is 2, modified Nucleotide; and/or d) at least one 5'-uridine uridine _3' (5,-uu-3,) dinucleotide, wherein 5'-uridine is a 2'-modified nucleoside acid. The composition of paragraph [00879], wherein the RNAi agent comprises a 2,-modification selected from the group consisting of: 2,-deoxy, 2,-deoxy-2,-fluoro, 2,-0-mercapto, 2'-0-methoxyethyl (2,-〇·μ〇Ε), 2,-0-aminopropyl (2.-0-AP), 2'-0-dimethylaminoethyl (2'-〇-DMAOE), 2,-0-dimethylaminopropyl (2,-O-DMAP), 2'-fluorene-diaminomethylethoxyethyl (2'-〇-DMAEOE And 2'-〇-N-mercaptoacetamido (2·-〇-ΝΜΑ). The composition of paragraph [00879] wherein the RNAi agent comprises a blunt end. The composition of paragraph [00879] wherein the RNAi agent comprises a suspension having from 1 to 4 unpaired nucleotides. The composition of paragraph [00879], wherein the RNAi agent comprises an overhang at the 3'-end of the antisense 154740.doc-173. 201141489 version of the RNAi agent. The composition of paragraph [00879], wherein the rule agent is conjugated to one or more agents selected from the group consisting of diagnostic compounds, reporter groups, crosslinkers, nuclease-resistant portions, natural or unusual nucleosides Bases, lipophilic molecules, cholesterol, lipids, phytohemagglutinin, steroids, ursolic alcohol, agave, bitter yuan, diosgenin, Puyuan, (four), Sanzhuang, borrowing suffocating yuan, innocent, table wood Steroid-derived lithocholic acid, vitamins, carbohydrates, polydextrose, pullulan, chitin, polyglucosamine, synthetic carbohydrates, oligolactone 15-polymer, natural polymer, low molecular weight or medium molecular weight The polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein binds to the molecule of the integrin, polycation, peptide, polyamine, peptidomimetic and/or transferrin. The composition of paragraph [00879], wherein the RNAi agent is capable of inhibiting the expression of the P-ENaC gene in vitro by at least about 60% in H441 cells at a concentration of 1 〇 nM. The composition of paragraph [00879], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 70% in H441 cells at a concentration of 1 μM. The composition of paragraph [00879], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 80% in a concentration of 1 〇 nM in H441 cells. The composition of paragraph [00879], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 90% in a concentration of 10 nM in H441 cells. 154. The composition of paragraph [00879], wherein the RNAi has an EC50 of no more than about 0.1 nM. The composition of paragraph [00879] wherein the RNAi has an EC50 of no more than about 0.01 nM. The composition of paragraph [00879] wherein the RNAi has an EC50 of no more than about 0.001 nM. A composition comprising a RNAi agent, the RNAi agent comprising a first strand and a second strand, wherein the first strand and the second strand comprise 0, 1, 2 or 3 nucleotides respectively and are provided in Table 1 The β-EnaC has a specific first and second different RNAi agents of at least 15 contiguous nucleotides. The composition of paragraph [00899], wherein the composition comprises a second RNAi agent for β-ENaC. The composition of paragraph [00899] wherein the second strand is 30 or less nucleotides in length. The composition of paragraph [00899] wherein the first strand and the second strand form a duplex region of between 15 and 30 nucleotide pairs in length. The composition of paragraph [00899] wherein the length of the first strand and the second strand are independently from 19 to 23 nucleotides. The composition of paragraph [00899], wherein the RNAi agent comprises a modification that increases the stability of the RNAi agent in a biological sample or environment. The composition of paragraph [00899], wherein the RNAi agent comprises a phosphorothioate and/or a 2'-modified nucleotide. The composition of paragraph [00899], wherein the RNAi agent comprises: at least one 5'-uridine-adenine-3' (5'-ua-3.) dinucleotide, wherein urine 154740.doc -175- 201141489 Glycosides are 2'-modified nucleotides; and/or at least one 5,_uridine-guanine-3 (5-ug-3.) dinucleotide, wherein 5'-urine is 2'- Modified nucleotide; and/or at least one 5'-cytidine. adenine dinucleotide, wherein 5'-cellin is 2'-modified nucleotide; and/or at least one 5'- Uridine. Uridine-3, (5, _uu_3i) dinucleotide, wherein 5'-uridine is a 2'-modified nucleotide. The composition of paragraph [00899], wherein the RNAi agent comprises one or more 2,-modifications selected from the group consisting of: 2-deoxy, 2'-deoxy-2'-fluoro, 2'-〇- Indenyl, 2,-0-methoxyethyl (2-O-MOE), 2'-nonyl-aminopropyl (2,_〇_Ap), 2,_〇_dimethylaminoethyl (2'-0-DMA0E), 2,-〇-dimethylaminopropyl (2,_〇_DMAp), 2,·〇_dimethylaminoethoxyethyl (2·-〇·〇 ΜΑΕΟΕ) and 2,-〇-Ν-mercaptoacetamido (2·-〇-ΝΜΑ). The composition of paragraph [00899], wherein the tRNAi agent comprises a blunt end. The composition of paragraph [00899], wherein the RNAi agent comprises a suspension having from 1 to 4 unpaired nucleotides. The composition of paragraph [00899] wherein the RNAi agent comprises a pendant at the 3' end of the antisense strand. The composition of paragraph [00899], wherein the RNA is conjugated to one or more agents, and the agent is selected from the group consisting of: a diagnostic compound, a reporter group, a cross-linking agent, a portion that confers nuclease resistance, natural or non- Nucleoside, lipophilic, cholesterol, lipid, lectin, steroid, ursolic, agave saponin, diosgenin, anthraquinone, triterpenoid, saponin, innocent IS, table Wood alcohol-derived lithocholic acid, vitamins, carbohydrates 154740.doc •176· 201141489 substances, polydextrose, pullulan, chitin, polyglucosamine, synthetic carbohydrates, oligolactone 15-polymer , natural polymers, low molecular or medium molecular weight polymers, inulin, cyclodextrin, hyaluronic acid, proteins, protein binders, molecules that target integrins, polycations, peptides, polyamines, peptidomimetics and/or transport Ferritin. The composition of paragraph [00899], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 60% in a concentration of 10 nM in H441 cells. The composition of paragraph [00899], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 70% in a concentration of 10 nM in H441 cells. The composition of paragraph [00899], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 80% in a concentration of 10 nM in H441 cells. The composition of paragraph [00899], wherein the RNAi agent is capable of inhibiting the expression of the β-ENaC gene in vitro by at least about 90% in a concentration of 10 nM in H441 cells. The composition of paragraph [00899], wherein the RNAi has an EC50 of no more than about 0.1 nM, such as the composition of paragraph [00899], wherein the RNAi has an EC50 of no more than about 0.01 nM. The composition of paragraph [00899] wherein the RNAi has an EC50 of no more than about 0.001 nM. A method of treating a β-ENaC-associated disease in an individual comprising the following 154740.doc-177-201141489 step of administering to the individual a therapeutically effective amount of a composition comprising an RNAi agent comprising a sense share and an antisense stock Wherein the antisense strand comprises at least 15 contiguous nucleotides of 〇, 1, 2 or 3 nucleotides different from the antisense strand of the RNAi agent specific for β-ENaC provided in Table 1. The method of paragraph [00919], wherein the j3_ENaC-related disease is associated with cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and/or obesity blood pressure. The method of paragraph [00919] wherein the p_ENaC associated disease is cystic fibrosis. The method of paragraph [00919], wherein the method further comprises administering for cystic fibrosis, type 1 pseudoaldosterone (PHA丨), lider syndrome, blood pressure, poisoning, hypotonicemia, and/or Steps for other treatments for obesity-related hypertension. The method of paragraph [〇〇919], wherein the composition comprises a second RNAi agent for !3_ENaC. As in paragraph [〇〇919], 苴117^? +, on

』万沄其中該方法另外包含投與其 針對β-ENaC之RNAi劑的步驟。 如段落[00919]之方法 如段落[00919]之方法 如段落[00919]之方法 如段落[00919]之方法 何順序投與。 ，其另外包含投與其他治療。 ，其中其他治療為組合物。 ，其中其他治療為方法。 ，其中其他治療及RNAi劑可以任 一種抑制個體β-ENaC基 驟·向個體投與治療有效 因表現之方法， 量之包含RNAi劑 其包含以下步 之組合物，該 154740.doc •178· 201141489 RNAi劑包含有義股及反義股，其中反義股包含有〇、ι、2 或3個核苷酸與對表1中提供之(3_ENac具有特異性之RNAi 劑之反義股不同的至少15個連續核普酸。 如段落[00929]之方法，其中個體受p_ENaC相關疾病折 磨或易患β-ENaC相關疾病。 如段落[00929]之方法，其中該p_ENaC^a關疾病為囊腫 性纖維化、1型假醛固酮過少症（PHA1)、李德爾症候群、 高血壓 '鹼中毒、低鉀血症及/或肥胖相關之高血壓。 如段落[00929]之方法，其中p_ENaC相關疾病為囊腫性 纖維化。 如段落[00932]之方法，其另外包含投與其他治療。 如段落[00933]之方法，其中其他治療為組合物。 如段落[00933]之方法，其中其他治療為方法。 如段落[00933]之方法，其中其他治療&amp; RNAi劑可以任 何順序投與。 一種藥物，其用於包含RNAi劑之RNAi調配物中，該 RNAi劑包含有義股及反義股…該反義股包含有〇: 1、2或3個核苷酸與對表}*提供之p_ENaC具有特異性之 RNAi劑之反義股不同的至少15個連續核苷酸。 上述任何組合物為醫藥學上有效之調配物。 如段落[G0879]之組合物，其用於治療個體之p.ac相 關疾病的方法中’該方法包含向該個體投與治療有效量之 如段落[00879]之組合物的步驟。 .-種如段落_9]之組合物之用途，其用於製造用以 154740.doc •179· 201141489 治療β-ENaC相關疾病之藥物。 如段落[00940]之用途，其中該β-ENaC相關疾病為囊腫 性纖維化、1型假醛固酮過少症（PHA1)、李德爾症候群、 高血壓、鹼中毒、低鉀血症及/或肥胖相關之高血壓。 如段落[00879]之組合物，其中所有嘧啶為2Ό-曱基修飾 之核苦酸。 如段落[00899]之組合物，其中所有嘧啶為2'0-甲基修飾 之核苷酸。 | 【圖式簡單說明】 圖 1A-1B 描繪 RNAi 劑 AD20807、AD20826、AD2083 2、 AS20834、AD20848 及 AD20861 活體内阻斷 β-ENaC 活性的 能力。 圖2A-2C描繪β-ENaC RNAi劑AD20832對人類支氣管上 皮細胞中ENaC通道功能活性之活體外作用。 154740.doc 180- 201141489 序列表 &lt;110&gt;瑞士商諾華公司 &lt;120&gt;用於治療β-ENaC相關疾病之有機組合物 &lt;130&gt; 54121 &lt;140〉 100114186 &lt;141&gt; 2011-04-22 &lt;150&gt; 61/327,379; 61/333,398 &lt;151&gt; 2010-04-23; 2010-05-11 &lt;160&gt; 4B0 &lt;170&gt; Patentln version 3.5 &lt;210&gt; 1 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 1 cagugacuac aacacgacc 19 &lt;210&gt; 2 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 2 ggucguguug uagucacug 19 &lt;210&gt; 3 &lt;211&gt; 19 &lt;212&gt; RNA &lt;2ί3&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 3 augacagaga aggcacuuc 19 9NA/VX 41 R Λ &gt; &gt; &gt; &gt; 0123 1111 2222 V V V &lt; &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 4 gaagugccuu cucugucau &lt;210&gt; 5 &lt;211&gt; 19 154740-序列表.doc 19 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 5 gugaagaagu accugcuga &lt;210&gt; 6 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 6 ucagcaggua cuucuucac &lt;210&gt; 7 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 7 gugacuacaa cacgaccua &lt;210&gt; 8 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 8 uaggucgugu uguagucac &lt;210&gt; 9 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 9 gguggaggcc cacaccaac &lt;210&gt; 10 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740·序列表.doc 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 10 guuggugugg gccuccacc &lt;210&gt; 11 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 11 ugguggaggc ccacaccaa &lt;210&gt; 12 &lt;211&gt; 19The method further comprises the step of administering a RNAi agent against β-ENaC. The method of paragraph [00919] is as described in paragraph [00919], such as the method of paragraph [00919], such as the method of paragraph [00919]. It additionally includes other treatments. Among other treatments are compositions. Among other treatments as methods. And wherein the other therapeutic and RNAi agents can inhibit the expression of the therapeutically effective cause of the individual β-ENaC based on the individual, and the RNAi agent comprises the composition of the following steps, the 154740.doc •178· 201141489 The RNAi agent comprises a sense strand and an antisense strand, wherein the antisense strand comprises at least ι, ι, 2 or 3 nucleotides different from the antisense strand of the RNAi agent specified in Table 1 (3_ENac specific) The method of paragraph [00929], wherein the individual is afflicted with a p_ENaC-related disease or is susceptible to a β-ENaC-related disease. The method of paragraph [00929], wherein the p_ENaC^a disease is a cystic fiber , type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension 'alkaline poisoning, hypokalemia and/or obesity-related hypertension. The method of paragraph [00929], wherein the p_ENaC-related disease is cystic Fibrosis. The method of paragraph [00932], which additionally comprises administering other treatments, such as the method of paragraph [00933], wherein the other treatment is a composition, such as the method of paragraph [00933], wherein the other treatment is a method. [00933] The method wherein the other therapeutic &amp; RNAi agents can be administered in any order. A drug for use in an RNAi formulation comprising a RNAi agent comprising a sense share and an antisense stock... the antisense stock comprises: 1, 2 or 3 nucleotides differ from at least 15 contiguous nucleotides of the antisense strand of the RNAi agent specific for p_ENaC provided in Table *. Any of the above compositions are pharmaceutically effective formulations. A composition of paragraph [G0879] for use in a method of treating a p. ac-related disease in a subject, the method comprising the step of administering to the individual a therapeutically effective amount of the composition of paragraph [00879]. The use of the composition of paragraph _9 for the manufacture of a medicament for the treatment of a β-ENaC-related disease, 154740.doc • 179. 201141489. The use of the method according to paragraph [00940], wherein the β-ENaC-related disease is a cyst Sexual fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and/or obesity-related hypertension. The composition of paragraph [00879], wherein all pyrimidines are 2Ό-曱-modified nuclear acid. As paragraph [00899] a composition in which all pyrimidines are 2'0-methyl modified nucleotides. | [Simplified illustration] Figures 1A-1B depict RNAi agents AD20807, AD20826, AD2083 2, AS20834, AD20848, and AD20861 in vivo blocking beta - ENaC ability to activate. Figures 2A-2C depict the in vitro effects of the β-ENaC RNAi agent AD20832 on ENaC channel functional activity in human bronchial epithelial cells. 154740.doc 180- 201141489 Sequence Listing &lt;110&gt;Swiss Business Novartis &lt;120&gt; Organic Composition for the Treatment of β-ENaC Related Diseases &lt;130&gt; 54121 &lt;140> 100114186 &lt;141&gt; 2011-04- 22 &lt;150&gt;61/327,379; 61/333,398 &lt;151&gt;2010-04-23; 2010-05-11 &lt;160&gt; 4B0 &lt;170&gt; Patentln version 3.5 &lt;210&gt; 1 &lt;211&gt; 19 &lt;;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 1 cagugacuac aacacgacc 19 &lt;210&gt; 2 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 2 ggucguguug uagucacug 19 &lt;210&gt; 3 &lt;211&gt; 19 &lt;212&gt; RNA &lt;2ί3&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 3 augacagaga aggcacuuc 19 9NA/VX 41 R Λ &gt;&gt;&gt;&gt; 0123 1111 2222 VVV &lt;&lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 4 gaagugccuu cucugucau &lt;210&gt; 5 &lt;211&gt; 19 154740-Sequence Listing.doc 19 201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 5 gugaagaa Gu accugcuga &lt;210&gt; 6 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 6 ucagcaggua cuucuucac &lt;210&gt; 7 &lt;211&gt;&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 7 gugacuacaa cacgaccua &lt;210&gt; 8 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 8 uaggucgugu uguagucac &lt;210&gt; 9 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 9 gguggaggcc cacaccaac &lt;210&gt; 10 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 · Sequence Listing.doc 201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 10 guuggugugg gccuccacc &lt;;210&gt;11&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 11 ugguggaggc ccacaccaa &lt;210&gt; 12 &lt;211&gt;

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 12 uugguguggg ccuccacca &lt;210&gt; 13 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 13 uuccaagacc acaugaucc &lt;210&gt; 14 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 14 ggaucaugug gucuuggaa &lt;210&gt; 15 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 154740·序列表.doc 201141489 &lt;400&gt; 15 agcugggagg ucagcgucu 19 &lt;210&gt; 16 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 16 agacgcugac cucccagcu 19 &lt;210&gt; 17 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; 19&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 12 uugguguggg ccuccacca &lt;210&gt; 13 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 13 uuccaagacc acaugaucc &lt;210&gt; 14 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;4〇〇&gt; 14 ggaucaugug gucuuggaa &lt;210&gt; 15 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi agent 154740 · Sequence Listing.doc 201141489 &lt;400&gt; 15 agcugggagg ucagcgucu 19 &lt;210&gt; 16 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 16 agacgcugac cucccagcu 19 &lt;210&gt; 17 &lt;211&gt; 19 &lt;;212&gt; RNA &lt;213&gt;Labor&lt;220&gt; 19

&lt;223&gt; RNAi 劑 &lt;400&gt; 17 gggagaaaua cugcaacaa &lt;210&gt; 18 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 18 uuguugcagu auuucuccc 19 &lt;210&gt; 19 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; 19&lt;223&gt; RNAi agent &lt;400&gt; 17 gggagaaaua cugcaacaa &lt;210&gt; 18 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 18 uuguugcagu auuucuccc 19 &lt;210&gt; 19 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;

&lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 19 ccaguuuggc uucuggaug &lt;210&gt; 20 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 20 cauccagaag ccaaacugg 19 154740·序列表.doc 201141489 &lt;210&gt; 21 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 21 agugacuaca acacgaccu 19 &lt;210&gt; 22 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 22 19 19 aggucguguu guagucacu&lt;2 2 3&gt; RNAi agent &lt;400&gt; 19 ccaguuuggc uucuggaug &lt;210&gt; 20 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; Cauccagaag ccaaacugg 19 154740 · Sequence Listing.doc 201141489 &lt;210&gt; 21 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 21 agugacuaca acacgaccu 19 &lt;210&gt; 22 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 22 19 19 aggucguguu guagucacu

&lt;210&gt; 23 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 23 aauaucaccc ugagcagga &lt;210&gt; 24 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 24 uccugcucag ggugauauu 19 &lt;210&gt; 25 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 25 ccugcaggcc accaacauc 19 &lt;210&gt; 26 &lt;211&gt; 19 154740-序列表.doc 19201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 26 gauguuggug gccugcagg &lt;210&gt; 27 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 27 aucacccuga gcaggaagg 19 &lt;210&gt; 28 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 28 ccuuccugcu cagggugau 19 &lt;210&gt; 29 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 29 gcugggaggu cagcgucuc 19 &lt;210&gt; 30 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 30 gagacgcuga ccucccagc 19 &lt;210&gt; 31 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 31 gagcugggag gucagcguc &lt;210&gt; 32 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 32 gacgcugacc ucccagcuc &lt;210&gt; 33 &lt;211&gt; 19&lt;210&gt; 23 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 23 aauaucacc ugagcagga &lt;210&gt; 24 &lt;211&gt; 19 &lt;212&gt RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 24 uccugcucag ggugauauu 19 &lt;210&gt; 25 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;;223&gt; RNAi agent &lt;400&gt; 25 ccugcaggcc accaacauc 19 &lt;210&gt; 26 &lt;211&gt; 19 154740-SEQ ID.doc. 19201141489 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 26 gauguuggug gccugcagg &lt;210&gt; 27 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 27 aucacccuga gcaggaagg 19 &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 28 ccuuccugcu cagggugau 19 &lt;210&gt;29 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi Agent &lt;400&gt; 29 gcugggaggu cagcgucuc 19 &lt;210&gt; 30 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 30 gagacgcuga ccucccagc 19 &lt;210&gt; 31 &lt;211&gt; 19 &lt;212&gt; RNA &lt;;213&gt; Artificial 154740 - Sequence Listing.doc 201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 31 gagcugggag gucagcguc &lt;210&gt;32 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 32 gacgcugacc ucccagcuc &lt;210&gt; 33 &lt;211&gt; 19

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 33 guggccaguu uggcuucug &lt;210&gt; 34 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 34 cagaagccaa acuggccac &lt;210&gt; 35 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 35 caguuuggcu ucuggaugg &lt;210&gt; 36 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740-序列表.doc 201141489 &lt;400&gt; 36 ccauccagaa gccaaacug &lt;210&gt; 37 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 37 ggccaguuug gcuucugga &lt;210&gt; 38 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 38 uccagaagcc aaacuggcc &lt;210&gt; 39 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 39 cuggguggcc aguuuggcu &lt;210&gt; 40 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 40 agccaaacug gccacccag &lt;210&gt; 41 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 41 ucuacaguga cuacaacac 154740-序列表.doc 201141489 &lt;210&gt; 42 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400〉 42 guguuguagu cacuguaga &lt;210&gt; 43 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 43 gcaugacaga gaaggcacu&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 33 guggccaguu uggcuucug &lt;210&gt; 34 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 34 cagaagccaa acuggccac &lt;210&gt; 35 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 35 caguuuggcu ucuggaugg &lt;210&gt; 36 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent 154740 - Sequence Listing.doc 201141489 &lt;400&gt; 36 ccauccagaa gccaaacug &lt;210&gt 37 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 37 ggccaguuug gcuucugga &lt;210&gt; 38 &lt;211&gt; 19 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 38 uccagaagcc aaacuggcc &lt;210&gt; 39 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; Agent &lt;400&gt; 39 cuggguggcc aguuuggcu &lt;210&gt; 40 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 40 agccaaacug gccacccag &lt;210&gt; 41 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 41 ucuacaguga cuacaacac 154740 - Sequence Listing.doc 201141489 &lt;210&gt; 42 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 42 guguuguagu cacuguaga &lt;;210&gt; 43 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 43 gcaugacaga gaaggcacu

&lt;210&gt; 44 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 44 agugccuucu cugucaugc &lt;210&gt; 45 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 45 auaucacccu gagcaggaa &lt;21〇&gt; 46 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 46 uuccugcuca gggugauau &lt;210&gt; 47 &lt;211&gt; 19 154740·序列表.doc 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 47 cuacagugac uacaacacg &lt;210&gt; 48 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 48 cguguuguag ucacuguag &lt;210&gt; 49 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 RNAi 劑 &lt;400&gt; 49 uaucacccug agcaggaag &lt;210&gt; 50 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 50 cuuccugcuc agggugaua &lt;210&gt; 51 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 51 ugcaggccac caacaucuu &lt;210&gt; 52 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;40〇&gt; 52 aagauguugg uggccugca 19 &lt;210&gt; 53 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 53 caugacagag aaggcacuu 19 &lt;210&gt; 54 &lt;211&gt; &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 54 aagugccuuc ucugucaug 19 &lt;210&gt; 55 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 55 ugaagaagua ccugcugaa 19 &lt;210&gt; 56 &lt;211&gt; 赢 &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 56 uucagcaggu acuucuuca 19 &lt;210&gt; 57 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 -11 - 154740-序列表.doc 201141489 &lt;400&gt; 57 gcugguggag gcccacacc &lt;210&gt; 58 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 58 ggugugggcc uccaccagc &lt;210&gt; 59 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 59 uacagugacu acaacacga &lt;210&gt; 60 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;4〇〇&gt; 60 ucguguugua gucacugua &lt;210&gt; 61 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 61 acagagaagg cacuuccuu &lt;210&gt; 62 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 62 aaggaagugc cuucucugu 154740-序列表.doc 201141489 &lt;210&gt; 63 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 63 acagugacua caacacgac 19 &lt;210&gt; 64 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 64 gucguguugu agucacugu 19&lt;210&gt; 44 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 44 agugccuucu cugucaugc &lt;210&gt; 45 &lt;211&gt; 19 &lt;212&gt RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 45 auaucacccu gagcaggaa &lt;21〇&gt; 46 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 46 uuccugcuca gggugauau &lt;210&gt; 47 &lt;211&gt; 19 154740·SEQ ID>>doc 201141489 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 47 cuacagugac uacaacacg &lt;210&gt; 48 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 48 cguguuguag ucacuguag &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial &lt;220&gt;&lt;2 2 RNAi agent &lt;400&gt; 49 uaucacccug agcaggaag &lt;210&gt; 50 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;; Artificial &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 50 cuuccugcuc agggugaua &lt;210&gt; 51 &lt;211&gt; 19 &Lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 51 ugcaggccac caacaucuu &lt;210&gt; 52 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740-preface List .doc 201141489 &lt;220&gt;&lt;223&gt; RNAi &lt;40〇&gt; 52 aagauguugg uggccugca 19 &lt;210&gt; 53 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt; 223 &gt; RNAi &lt;400&gt; 53 caugacagag aaggcacuu 19 &lt;210&gt; 54 &lt;211&gt;&lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;4〇〇&gt; 54 aagugccuuc ucugucaug 19 &lt;210&gt; 55 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 55 ugaagaagua ccugcugaa 19 &lt;210&gt; 56 &lt;211&gt ; win &lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 56 uucagcaggu acuucuuca 19 &lt;210&gt; 57 &lt;211&gt;&lt;212&gt;&lt;213&gt; RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent-11 - 154740 - Sequence Listing.doc 201141489 &lt;400&gt; 57 Gcugguggag gcccacacc &lt;210&gt; 58 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 58 ggugugggcc uccaccagc &lt;210&gt; 59 &lt;211&gt; 19 &lt;;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 59 uacagugacu acaacacga &lt;210&gt; 60 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;4〇〇&gt; 60 ucguguugua gucacugua &lt;210&gt; 61 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 61 acagagaagg cacuuccuu &lt;210&gt; 62 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 62 aaggaagugc cuucucugu 154740 - Sequence Listing.doc 201141489 &lt;210&gt;63&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 63 acagugacua caacacgac 19 &lt;210&gt; 64 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 64 gucguguugu agucacugu 19

&lt;210&gt; 65 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 含&gt; RNAi 劑 &lt;4〇〇&gt; 65 ugagcuggga ggucagcgu 19&lt;210&gt; 65 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 &gt; RNAi agent &lt;4〇〇&gt; 65 ugagcuggga ggucagcgu 19

&lt;210&gt; 66 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 66 acgcugaccu cccagcuca 19 &lt;210&gt; 67 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 67 uggccaguuu ggcuucugg 19 &lt;210&gt; 68 &lt;211&gt; 19 154740-序列表.doc •13· 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 68 ccagaagcca aacuggcca 19 &lt;210&gt; 69 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 69 ugucucagga gcgggacca 19 &lt;210&gt; 70 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 70 uggucccgcu ccugagaca&lt;210&gt; 66 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 66 acgcugaccu cccagcuca 19 &lt;210&gt; 67 &lt;211&gt;&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 67 uggccaguuu ggcuucugg 19 &lt;210&gt; 68 &lt;211&gt; 19 154740 - Sequence Listing.doc •13·201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 68 ccagaagcca aacuggcca 19 &lt;210&gt; 69 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 69 ugucucagga gcgggacca 19 &lt;210&gt; 70 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 70 uggucccgcu Ccugagaca

19 &lt;210&gt; 71 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 71 guggaggccc acaccaacu 19 &lt;210&gt; 72 &lt;211&gt; 19 &lt;212&gt; RMA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 72 aguuggugug ggccuccac19 &lt;210&gt; 71 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 71 guggaggccc acaccaacu 19 &lt;210&gt; 72 &lt;211&gt; 19 &lt;;212&gt; RMA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi Agent &lt;400&gt; 72 aguuggugug ggccuccac

19 &lt;210&gt; 73 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc • 14· 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 73 ggguggccag uuuggcuuc &lt;210&gt; 74 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 74 gaagccaaac uggccaccc &lt;210&gt; 75 &lt;211&gt; 1919 &lt;210&gt; 73 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 - Sequence Listing.doc • 14·201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 73 ggguggccag uuuggcuuc &lt;210&gt; 74 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 74 gaagccaaac uggccaccc &lt;210&gt; 75 &lt;211&gt;

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 75 gguggccagu uuggcuucu &lt;210&gt; 76 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 76 agaagccaaa cuggccacc &lt;210&gt; 77 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 77 ucacccugag caggaaggg &lt;210&gt; 78 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740-序列表.doc 201141489 &lt;400&gt; 78 cccuuccugc ucaggguga &lt;210&gt; 79 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 79 gccaguuugg cuucuggau &lt;210&gt; 80 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 80 auccagaagc caaacuggc &lt;210&gt; 81 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 81 agcuggugga ggcccacac &lt;210&gt; 82 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 82 gugugggccu ccaccagcu &lt;210&gt; 83 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 83 aucuccaugg cugacuggc 154740-序列表.doc 201141489 &lt;210&gt; 84 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 84 gccagucagc cauggagau 19 &lt;210&gt; 85 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 85&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 75 gguggccagu uuggcuucu &lt;210&gt; 76 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 76 agaagccaaa cuggccacc &lt;210&gt; 77 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 77 ucacccugag Caggaaggg &lt;210&gt; 78 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 154740 - Sequence Listing.doc 201141489 &lt;400&gt; 78 cccuuccugc ucaggguga &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 79 gccaguuugg cuucuggau &lt;210&gt; 80 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 80 auccagaagc caaacuggc &lt;210&gt; 81 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi Agent &lt;400&gt; 81 agcuggugga ggcccacac &lt;210&gt; 82 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 82 gugugggccu ccaccagcu &lt;210&gt; 83 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 83 aucuccaugg cugacuggc 154740 - Sequence Listing.doc 201141489 &lt;210&gt; 84 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 84 gccagucagc cauggagau 19 &lt;210&gt; 85 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt;

ggcaugacag agaaggcac 19 &lt;210〉 86 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 86 gugccuucuc ugucaugcc 19 &lt;210&gt; 87 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 87 19 ggagaaauac ugcaacaac &lt;210&gt; 88 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 88 guuguugcag uauuucucc 19 &lt;210&gt; 89 &lt;211&gt; 19 -17- 154740-序列表.doc 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 89 uggguggcca guuuggcuu &lt;210&gt; 90 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 90 aagccaaacu ggccaccca &lt;210&gt; 91 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 91 gagcuggugg aggcccaca &lt;210&gt; 92 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 92 ugugggccuc caccagcuc &lt;210&gt; 93 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 93 gacagagaag gcacuuccu &lt;21〇&gt; 94 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc 19201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 94 aggaagugcc uucucuguc &lt;210&gt; 95 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 95 aguuuggcuu cuggauggg 19 &lt;210&gt; 96 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 96 cccauccaga agccaaacu 19 &lt;210&gt; 97 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 97 ugacagagaa ggcacuucc 19 &lt;210&gt; 98 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 98 ggaagugccu ucucuguca 19 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; &lt;220&gt; &lt;223&gt; A工 9 9 N IV 91 R/ 154740·序列表.doc 19- c. 201141489 &lt;400&gt; 99 gaagaaguac cugcugaag &lt;210&gt; 100 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 100 cuucagcagg uacuucuuc &lt;210&gt; 101 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 101 ucuccauggc ugacuggcc &lt;210&gt; 102 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 102 ggccagucag ccauggaga &lt;210&gt; 103 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 103 cugguggagg cccacacca &lt;210&gt; 104 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 104 uggugugggc cuccaccag 154740-序列表.doc 19 201141489 &lt;210&gt; 105 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 105 cagagaaggc acuuccuuc &lt;210&gt; 106 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 106 19Ggcaugacag agaaggcac 19 &lt;210> 86 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 86 gugccuucuc ugucaugcc 19 &lt;210&gt; 87 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 87 19 ggagaaauac ugcaacaac &lt;210&gt; 88 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 88 guuguugcag uauuucucc 19 &lt;210&gt; 89 &lt;211&gt; 19-17-154740-sequence table.doc 201141489 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 89 uggguggcca guuuggcuu &lt;210&gt; 90 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 90 aagccaaacu ggccaccca &lt;210&gt; 91 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 91 gagcuggugg aggcccaca &lt;210&gt; 92 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;4〇〇&gt; 92 ugugggcc Uc caccagcuc &lt;210&gt; 93 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 93 gacagagaag gcacuuccu &lt;21〇&gt; 94 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 - Sequence Listing.doc 19201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 94 aggaagugcc uucucuguc &lt;210&gt; 95 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 95 aguuuggcuu cuggauggg 19 &lt;210&gt; 96 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 96 cccauccaga agccaaacu 19 &lt;210&gt; 97 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 97 ugacagagaa ggcacuucc 19 &lt;;210&gt; 98 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 98 ggaagugccu ucucuguca 19 &lt;210&gt;&lt;211&gt;&lt;212&gt;;213&gt;&lt;220&gt;&lt;223&gt; A work 9 9 N IV 91 R/ 154740·sequence table.doc 19- c. 201141489 &lt;4 99&gt;100&lt;212&gt;&lt 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 101 ucuccauggc ugacuggcc &lt;210&gt; 102 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 102 ggccagucag ccauggaga &lt;210&gt; 103 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 103 cugguggagg cccacacca &lt;210&gt; 104 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 104 uggugugggc cuccaccag 154740 - Sequence Listing. 19 201141489 &lt;210&gt; 105 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 105 cagagaaggc acuuccuuc &lt;210&gt; 106 &lt;211&gt; 19 &lt;;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 106 1 9

gaaggaagug ccuucucugGaaggaagug ccuucucug

7 A工 09 N L 11 R 乂 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 107 cugcaggcca ccaacaucu &lt;210&gt; 108 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 108 agauguuggu ggccugcag &lt;210&gt; 109 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 109 gggcaugaca gagaaggca &lt;210&gt; 110 &lt;211&gt; 19 19 19 19 154740-序列表.doc -21 - 19201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 110 ugccuucucu gucaugccc &lt;21〇&gt; 111 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 111 cagugacuac aacacgacc 19 &lt;210&gt; 112 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 112 ggucguguug uagucacug 19 &lt;210&gt; 113 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 113 augacagaga aggcacuuc 19 &lt;210&gt; 114 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 114 gaagugccuu cucugucau 19 &lt;210&gt; 115 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc •22· 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 115 gugaagaagu accugcuga &lt;210&gt; 116 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 116 ucagcaggua cuucuucac &lt;210&gt; 117 &lt;211&gt; 197 A work 09 NL 11 R 乂 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 107 cugcaggcca ccaacaucu &lt;210&gt; 108 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 108 agauguuggu ggccugcag &lt;210&gt; 109 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 109 gggcaugaca gagaaggca &lt;210&gt; 110 &lt;211&gt; 19 19 19 19 154740 - Sequence Listing.doc -21 - 19201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 110 ugccuucucu gucaugccc &lt;21〇&gt; 111 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 111 cagugacuac aacacgacc 19 &lt;210&gt; 112 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 112 ggucguguug uagucacug 19 &lt;210&gt; 113 &lt; 211 &gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &Lt;400&gt; 113 augacagaga aggcacuuc 19 &lt;210&gt; 114 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 114 gaagugccuu cucugucau 19 &lt;210&gt; 115 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 - Sequence Listing.doc •22·201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 115 gugaagaagu accugcuga &lt;210&gt; 116 &lt; 211 &gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 116 ucagcaggua cuucuucac &lt;210&gt; 117 &lt;211&gt;

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 117 gugacuacaa cacgaccua &lt;210&gt; 118 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 118 uaggucgugu uguagucac &lt;210&gt; 119 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 119 gguggaggcc cacaccaac &lt;210&gt; 120 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740-序列表.doc 201141489 &lt;400&gt; 120 guuggugugg gccuccacc &lt;210&gt; 121 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 121 ugguggaggc ccacaccaa &lt;210&gt; 122 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 122 uugguguggg ccuccacca &lt;210&gt; 123 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 123 uuccaagacc acaugaucc &lt;210&gt; 124 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 124 ggaucaugug gucuuggaa &lt;210&gt; 125 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 125 agcugggagg ucagcgucu 154740-序列表.doc 19 201141489 &lt;210&gt; 126 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 126 agacgcugac cucccagcu &lt;210&gt; 127 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 127&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 117 gugacuacaa cacgaccua &lt;210&gt; 118 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 118 uaggucgugu uguagucac &lt;210&gt; 119 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 119 gguggaggcc Cacaccaac &lt;210&gt; 120 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 154740 - Sequence Listing.doc 201141489 &lt;400&gt; 120 guuggugugg gccuccacc &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 121 ugguggaggc ccacaccaa &lt;210&gt; 122 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 122 uugguguggg ccuccacca &lt;210&gt; 123 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 123 uuccaagacc acaugaucc &lt;210&gt; 124 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 124 ggaucaugug gucuuggaa &lt;210&gt; 125 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 125 agcugggagg ucagcgucu 154740 - Sequence Listing.doc 19 201141489 &lt;210&gt; 126 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 126 agacgcugac cucccagcu &lt;210&gt; 127 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt;

19 gggagaaaua cugcaacaa &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;19 gggagaaaua cugcaacaa &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;

&lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 128 uuguugcagu auuucuccc &lt;210&gt; 129 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 129 ccaguuuggc uucuggaug &lt;210&gt; 130 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 130 cauccagaag ccaaacugg &lt;210&gt; 131 &lt;211&gt; 19 19 19 19 154740-序列表.doc •25- 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 131 agugacuaca acacgaccu &lt;210&gt; 132 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 132 aggucguguu guagucacu &lt;210&gt; 133 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 133 aauaucaccc ugagcagga &lt;210&gt; 134 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 134 uccugcucag ggugauauu &lt;210&gt; 135 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 128 uuguugcagu auuucuccc &lt;210&gt; 129 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 129 ccaguuuggc uucuggaug &lt;210&gt; 130 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 130 cauccagaag ccaaacugg &lt;210&gt; 131 &lt;211&gt; 19 19 19 19 154740-Sequence Listing.doc •25-201141489 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 131 agugacuaca acacgaccu &lt;210&gt; 132 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;4〇〇&gt; 132 aggucguguu guagucacu &lt;210&gt; 133 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 133 aauaucacc ugagcagga &lt;210&gt; 134 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 134 uccugcucag ggugauauu &lt;210&gt; 135 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;

&lt;223&gt; RNAi 劑 &lt;400&gt; 13S ccugcaggcc accaacauc &lt;210&gt; 136 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 136 gauguuggug gccugcagg &lt;210&gt; 137 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 137 aucacccuga gcaggaagg &lt;210&gt; 138 &lt;211&gt; 19&lt;223&gt; RNAi agent &lt;400&gt; 13S ccugcaggcc accaacauc &lt;210&gt; 136 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 - Sequence Listing.doc 201141489 &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 136 gauguuggug gccugcagg &lt;210&gt; 137 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 137 aucacccuga gcaggaagg &lt;210&gt; 138 &lt;;211&gt; 19

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 138 ccuuccugcu cagggugau &lt;210&gt; 139 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 139 gcugggaggu cagcgucuc &lt;210&gt; 140 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 140 gagacgcuga ccucccagc &lt;210&gt; 141 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740-序列表.doc 201141489 &lt;400&gt; 141 gagcugggag gucagcguc &lt;210&gt; 142 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 142 gacgcugacc ucccagcuc &lt;210&gt; 143 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 143 guggccaguu uggcuucug &lt;210&gt; 144 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 144 cagaagccaa acuggccac &lt;210&gt; 145 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 145 caguuuggcu ucuggaugg &lt;210&gt; 146 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 146 ccauccagaa gccaaacug 154740·序列表.doc 19201141489 &lt;210&gt; 147 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 147 ggccaguuug gcuucugga &lt;210&gt; 148 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 148 uccagaagcc aaacuggcc 19 &lt;210&gt; 149 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 149 cuggguggcc aguuuggcu 19 &lt;210&gt; 150 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 150 agccaaacug gccacccag 19 &gt; &gt; &gt; Λ 012 3 1111 22 2 2 &lt; &lt; &lt; &lt; I A工 5 9 N j II R Λ &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 151 ucuacaguga cuacaacac &lt;210&gt; 152 &lt;211&gt; 19 -29- 19 154740·序列表,doc 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 152 guguuguagu cacuguaga 19 &lt;210&gt; 153 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 153 gcaugacaga gaaggcacu 19 &lt;210&gt; 154 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 154 agugccuucu cugucaugc&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 138 ccuuccugcu cagggugau &lt;210&gt; 139 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 139 gcugggaggu cagcgucuc &lt;210&gt; 140 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; Gagacgcuga ccucccagc &lt;210&gt; 141 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 154740 - Sequence Listing.doc 201141489 &lt;400&gt; 141 gagcugggag gucagcguc &lt;210&gt; 142 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 142 gacgcugacc ucccagcuc &lt;210&gt; 143 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 143 guggccaguu uggcuucug &lt;210&gt; 144 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 144 cagaagccaa acuggccac &lt;210&gt; 145 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 145 caguuuggcu ucuggaugg &lt;210&gt; 146 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 146 ccauccagaa gccaaacug 154740. Sequence listing. doc 19201141489 &lt;210&gt; 147 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 &gt; RNAi agent &lt;400&gt; 147 ggccaguuug gcuucugga &lt;210&gt; 148 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 148 uccagaagcc aaacuggcc 19 &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 149 cuggguggcc aguuuggcu 19 &lt;210&gt; 150 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 150 agccaaacug gccacccag 19 &gt;&gt;&gt; 012 012 3 1111 22 2 2 &lt;&lt;&lt;&lt;&lt; IA work 5 9 N j II R Λ &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 151 ucuacaguga cuacaacac &lt;210&gt; 152 &lt;211&gt; 19 -29- 19 154740· Sequence Listing, doc 201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 152 guguuguagu cacuguaga 19 &lt;210&gt; 153 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 153 gcaugacaga gaaggcacu 19 &lt;210&gt; 154 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 154 agugccuucu cugucaugc

19 &lt;210&gt; 155 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 155 auaucacccu gagcaggaa 19 &lt;210&gt; 156 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 156 uuccugcuca gggugauau19 &lt;210&gt; 155 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 155 auaucacccu gagcaggaa 19 &lt;210&gt; 156 &lt;211&gt; 19 &lt;;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 156 uuccugcuca gggugauau

19 &lt;210&gt; 157 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc -30- 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 157 cuacagugac uacaacacg &lt;210&gt; 158 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 158 cguguuguag ucacuguag &lt;210&gt; 159 &lt;211&gt; 1919 &lt;210&gt; 157 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740 - Sequence Listing. doc -30 - 201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 157 cuacagugac uacaacacg &lt;210&gt; 158 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 158 cguguuguag ucacuguag &lt;210&gt; 159 &lt;211&gt;

&lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 159 uaucacccug agcaggaag &lt;210&gt; 160 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 160 cuuccugcuc agggugaua &lt;210&gt; 161 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 161 ugcaggccac caacaucuu &lt;210&gt; 162 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740_ 序列表.doc 19201141489 &lt;400&gt; 162 aagauguugg uggccugca &lt;210&gt; 163 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 163 caugacagag aaggcacuu 19 &lt;210&gt; 164 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 164 aagugccuuc ucugucaug 19 &lt;210&gt; 165 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 165 ugaagaagua ccugcugaa 19 &lt;210&gt; 166 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 166 uucagcaggu acuucuuca 19 &lt;210&gt; 167 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 167 gcugguggag gcccacacc 154740·序列表.doc •32- 19 19 201141489&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 159 uaucacccug agcaggaag &lt;210&gt; 160 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 160 cuuccugcuc agggugaua &lt;210&gt; 161 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 161 ugcaggccac Caacaucuu &lt;210&gt; 162 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent 154740_ Sequence Listing.doc 19201141489 &lt;400&gt; 162 aagauguugg uggccugca &lt;210&gt; 163 &lt;;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 163 caugacagag aaggcacuu 19 &lt;210&gt; 164 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 164 aagugccuuc ucugucaug 19 &lt;210&gt; 165 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 165 ugaagaagua ccugcugaa 19 &lt;210&gt; 166 &lt;211&gt; 19 &lt;2 12&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 166 uucagcaggu acuucuuca 19 &lt;210&gt; 167 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 167 gcugguggag gcccacacc 154740. Sequence Listing.doc •32- 19 19 201141489

&lt;210&gt; 168 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 168 ggugugggcc uccaccagc &lt;210&gt; 169 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 169 uacagugacu acaacacga &lt;210&gt; 170 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 170 ucguguugua gucacugua &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 19&lt;210&gt; 168 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 168 ggugugggcc uccaccagc &lt;210&gt; 169 &lt;211&gt; 19 &lt;212&gt RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 169 uacagugacu acaacacga &lt;210&gt; 170 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 170 ucguguugua gucacugua &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 19 19

1 A工 7 9 N rv 1 1 R &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 171 acagdgaagg cacuuccuu 19 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 2 A工 79 N」 11 R/ &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 172 aaggaagugc cuucucugu 19 &lt;210&gt; 173 &lt;211&gt; 19 154740·序列表.doc 33· 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 173 acagugacua caacacgac &lt;210&gt; 174 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 174 gucguguugu agucacugu &lt;210&gt; 175 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 175 ugagcuggga ggucagcgu &lt;210&gt; 176 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 176 acgcugaccu cccagcuca &lt;210&gt; 177 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 177 uggccaguuu ggcuucugg &lt;210&gt; 178 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 178 ccagaagcca aacuggcca 19 &lt;210&gt; 179 &lt;21X&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 179 ugucucagga gcgggacca 19 &lt;210&gt; 180 &lt;211&gt; &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 180 uggucccgcu ccugagaca 19 &lt;210&gt; 181 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 181 guggaggccc acaccaacu 19 &lt;210&gt; 182 &lt;211&gt; 赢 &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 182 aguuggugug ggccuccac 19 &lt;210&gt; 183 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 c220&gt; &lt;223&gt; RNAi 劑 35- 154740-序列表.doc 201141489 &lt;400&gt; 183 ggguggccag uuuggcuuc &lt;210&gt; 184 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 184 gaagccaaac uggccaccc &lt;210&gt; 185 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 185 gguggccagu uuggcuucu &lt;210&gt; 186 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 186 agaagccaaa cuggccacc &lt;210&gt; 187 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 187 ucacccugag caggaaggg &lt;210&gt; 188 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 188 cccuuccugc ucaggguga 154740·序列表.doc 201141489 &lt;210&gt; 189 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 189 gccaguuugg cuucuggau &lt;210&gt; 190 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 190 auccagaagc caaacuggc1 A worker 7 9 N rv 1 1 R &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 171 acagdgaagg cacuuccuu 19 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 2 A worker 79 N" 11 R/ &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 172 aaggaagugc cuucucugu 19 &lt;210&gt; 173 &lt;211&gt; 19 154740 · Sequence Listing.doc 33· 201141489 &lt;212&gt; RNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 173 acagugacua caacacgac &lt;210&gt; 174 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi Agent&lt;220&gt;;400&gt; 174 gucguguugu agucacugu &lt;210&gt; 175 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 175 ugagcuggga ggucagcgu &lt;210&gt; 176 &lt; 211 &gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 176 acgcugaccu cccagcuca &lt;210&gt; 177 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 177 uggccaguuu ggcuucugg &lt;210&gt; 178 &lt;211&gt; 19 &lt;212&gt; NA &lt;213&gt; Artificial 154740 - Sequence Listing.doc 201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 178 ccagaagcca aacuggcca 19 &lt;210&gt; 179 &lt;21X&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 179 ugucucagga gcgggacca 19 &lt;210&gt; 180 &lt;211&gt;&lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 180 uggucccgcu ccugagaca 19 &lt;210&gt; 181 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 181 guggaggccc acaccaacu 19 &lt;210&gt; 182 &lt;211&gt; Win &lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 182 aguuggugug ggccuccac 19 &lt;210&gt; 183 &lt;211&gt;&lt;212&gt;&lt;;213&gt; 19 RNA artificial c220&gt;&lt;223&gt; RNAi agent 35-154740-sequence table.doc 201141489 &lt;400&gt; 183 ggguggccag uuuggcuuc &lt;210&gt; 184 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 184 gaagccaaac Uggccaccc &lt;210&gt; 185 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 185 gguggccagu uuggcuucu &lt;210&gt; 186 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 186 agaagccaaa cuggccacc &lt;210&gt; 187 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;;223&gt; RNAi agent &lt;400&gt; 187 ucacccugag caggaaggg &lt;210&gt; 188 &lt;2U&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 188 cccuuccugc ucaggguga 154740 Sequence Listing.doc 201141489 &lt;210&gt; 189 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 189 gccaguuugg cuucuggau &lt;210&gt; 190 &lt; 211 &gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 190 auccagaagc caaacuggc

&lt;210&gt; 191 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 191 agcuggugga ggcccacac &lt;210&gt; 192 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 192 gugugggccu ccaccagcu &lt;210&gt; 193 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 193 aucuccaugg cugacuggc &lt;210&gt; 194 &lt;211&gt; 19 154740-序列表.doc 19 201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 194 gccagucagc cauggagau &lt;210&gt; 195 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; 19 &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 195 ggcaugacag agaaggcac&lt;210&gt; 191 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 191 agcuggugga ggcccacac &lt;210&gt; 192 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 192 gugugggccu ccaccagcu &lt;210&gt; 193 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt; 223 &gt; RNAi &lt;400&gt; 193 aucuccaugg cugacuggc &lt;210&gt; 194 &lt;211&gt; 19 154740 - Sequence Listing.doc 19 201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;;400&gt; 194 gccagucagc cauggagau &lt;210&gt; 195 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt; 19 &lt;2 2 3&gt; RNAi agent &lt;400&gt; 195 ggcaugacag agaaggcac

&gt; &gt; &gt; &gt; 0123 1111 2 2 2 2 V V &lt; V A工 99 N」 1 1 R Λ 6 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 196 gugccuucuc ugucaugcc 19 &lt;210&gt; 197 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 197 ggagaaauac ugcaacaac 19 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 8 A工 99 N rv 11 R / &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 198 guuguugcag uauuucucc 19 &lt;210&gt; 199 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 154740-序列表.doc • 38 - 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 199 uggguggcca guuuggcuu 19 &lt;210&gt; 200 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 200 aagccaaacu ggccaccca 19 &lt;210&gt; 201 &lt;211〉 &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 201 gagcuggugg aggcccaca 19 &lt;210&gt; 202 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 202 ugugggccuc caccagcuc 19 &lt;210&gt; 203 &lt;211&gt; 赢 &lt;212&gt; • &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 203 gacagagaag gcacuuccu 19 &lt;210&gt; 204 &lt;211&gt; &lt;212&gt; &lt;213&gt; 19 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 39- 154740-序列表.doc 201141489 &lt;400&gt; 204 aggaagugcc uucucuguc &lt;210&gt; 205 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 205 aguuuggcuu cuggauggg &lt;210&gt; 206 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 206 cccauccaga agccaaacu &lt;210&gt; 207 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 207 ugacagagaa ggcacuucc &lt;210&gt; 208 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 208 ggaagugccu ucucuguca &lt;210&gt; 209 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 209 gaagaaguac cugcugaag 154740-序列表 _doc 201141489 &lt;210&gt; 210 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 210 cuucagcagg uacuucuuc &lt;210&gt; 211 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 211&gt;&gt;&gt;&gt; 0123 1111 2 2 2 2 VV &lt; VA work 99 N" 1 1 R Λ 6 &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 196 gugccuucuc ugucaugcc 19 &lt;210&gt;&lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 197 ggagaaauac ugcaacaac 19 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; A worker 99 N rv 11 R / &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 198 guuguugcag uauuucucc 19 &lt;210&gt; 199 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Artificial 154740-SEQ ID NO. .doc • 38 - 201141489 &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 199 uggguggcca guuuggcuu 19 &lt;210&gt; 200 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 200 aagccaaacu ggccaccca 19 &lt;210&gt; 201 &lt;211&gt;&lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 201 gagcuggugg aggcccaca 19 &lt;210&gt; 202 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA artificial &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 202 ugugggccuc caccagcuc 19 &lt;210&gt; 203 &lt;211&gt; Win &lt;212&gt; • &lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 203 gacagagaag gcacuuccu 19 &lt;210&gt; 204 &lt;211&gt;&lt;212&gt;&lt;213&gt; 19 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent 39-154740-SEQ ID NO.doc 201141489 &lt;400&gt; 204 aggaagugcc uucucuguc &lt;210&gt; 205 &lt;211&gt 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 205 aguuuggcuu cuggauggg &lt;210&gt; 206 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 206 cccauccaga agccaaacu &lt;210&gt; 207 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 207 ugacagagaa ggcacuucc &lt;210&gt; 208 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 208 ggaagugccu ucucuguca &lt;210&gt; 209 &lt;211&gt;&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 209 gaagaaguac cugcugaag 154740 - Sequence Listing _doc 201141489 &lt;210&gt; 210 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 210 cuucagcagg Uacuucuuc &lt;210&gt; 211 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt;

ucuccauggc ugacuggcc &lt;210&gt; 212 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 212 ggccagucag ccauggaga &lt;210&gt; 213 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 213 cugguggagg cccacacca &lt;210&gt; 214 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 214 uggugugggc cuccaccag &lt;210&gt; 215 &lt;211&gt; 19 154740·序列表.doc 19201141489 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 215 cagagaaggc acuuccuuc &lt;210&gt; 216 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 216 gaaggaagug ccuucucug 19 &lt;210&gt; 217 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 217 cugcaggcca ccaacaucu 19 &lt;210&gt; 218 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 218 agauguuggu ggccugcag 19 &lt;210&gt; 219 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 &lt;400&gt; 219 gggcaugaca gagaaggca 19 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 154740-序列表.doc -42-Ucuccauggc ugacuggcc &lt;210&gt; 212 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 212 ggccagucag ccauggaga &lt;210&gt; 213 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 213 cugguggagg cccacacca &lt;210&gt; 214 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 214 uggugugggc cuccaccag &lt;210&gt; 215 &lt;211&gt; 19 154740 · Sequence Listing.doc 19201141489 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 215 cagagaaggc acuuccuuc &lt;210&gt; 216 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 216 gaaggaagug ccuucucug 19 &lt;210&gt ; 217 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 217 cugcaggcca ccaacaucu 19 &lt;210&gt; 218 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 218 agaug Uuggu ggccugcag 19 &lt;210&gt; 219 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent &lt;400&gt; 219 gggcaugaca gagaaggca 19 &lt;210&gt;&lt;211&gt;;&lt;212&gt;&lt;213&gt; 154740-Sequence Listing.doc -42-

201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 220 ugccuucucu gucaugccc &lt;210&gt; 221 &lt;211&gt; 2280 &lt;212&gt; DNA &lt;213&gt;石蟹獼狼 &lt;400&gt; 221 ggtacccagc ttgcttgttc tttttgcaga agctcagaat aaacgctcaa ctttggcaga tcaattcccc ggggatccga attcgccacc atgcacgtga agaagtacct gctgaagtgc ctgcaccggc tgcagaaggg ccccggctac acgtacaagg agctgctggt gtggtactgc gataacacca acacccacgg ccccaagcgt atcatctgcg aggggcccaa gaagaaagcc gtgtggttcc tgctcaccct gctcttcact gctctcgtct gctggcagtg gggcatcttc atcaggacct acttgagctg ggaggtcagc gtctccctct ccgtaggctt caagaccatg gacttccccg ccgtcaccat ctgcaatgct agccccttca agtattccaa agtcaagcat ttgctgaagg acctggatga gctgatggaa gctgtcctgg agagaatcct ggctcctgag ctaagccatg ccaatgccac caggaccctg aactcttcca tctggaacca cacaccactg gtccttattg atgaacggaa cccccaccac cccatggtcc tcgatctctt tggagataac cacaatggct taacaaacag ctcagcatca gaaaagatct gtaatgccca tgggtgcaaa atggccatga gactatgtag cctcaacggg acccagtgca ccttccggaa cttcaccagc gctacccagg cagtgacaga gtggtacagc ctgcaggcca ccaacatctt tgcgcaggtg ccgcagcagg agctggtgga gatgagctac cccggcgagc agatgatcct ggcctgcctg tttggagctg agccctgcaa ctaccggaac ttcacgtcca tcttctaccc tcactatggc aactgttaca tcttcaactg gggcatgaca gagaaggcac ttccttcggc caaccctgga cctgaatttg gcctgaagtt gatcctggac ataggccagg aagactacgt ccccttcctc gcgtccacgg ctggggtcag gctgatgctt cacgagcaga ggtcataccc cttcatcaga gacgagggca tctatgccat gtcggggaca gagacgtcca tcggggtact cgtggacaag cttcagcgca tgggggagcc ctacagcccg tgcaccgtga atggctccga ggtccccgtc caaaacttct acagtgacta caacacgacc tactccatcc aggcctgtct tcgctcctgc ttccaagacc acatgatccg tagctgcaag tgtgggcact acctctaccc actgccccgt ggggagaaat actgcaacaa ccgggacttc ccagactggg cccattgcta ctcagatctg cagatgagcg tggcgcagag agagacctgc attggcatgt gcaaggaatc ctgcaatgac acccagtaca agatgactat ctccatggct gactggcctt ctgaggcctc tgaggactgg 154740-序列表.doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 43- 1500 201141489 attttccacg tcttgtctca ggagcgggac caaagcacca atatcaccct gagcaggaag 1560 ggaattgtca agctcaacat ctacttccaa gaatttaact atcgcaccat tgaagaatca 1620 gcagccaata acctcgtctg gctgctctca aatctgggtg gccagtttgg cttctggatg 1680 gggggctctg tgctgtgcct catcgagttt ggggagatca tcatcgactt tgtgtggatc 1740 accatcatca agctggtggc cttggccaag agcctccggc agcggcgagc ccaagccagc 1800 tactccggcc caccgcccac ggtggctgag ctggtggagg cccacaccaa cttcggctac I860 cagcctgaca cggccccccg cagccccaac accgggccct accccagtga gcaggccctg 1920 cccatcccgg gcaccccgcc ccccaactat gactccctgc gtctgcagcc actggacgtc 1980 atcgagtctg acagtgaggg tgatgccatc taagcggccg cctagaaata gcttgatctg 2040 gttaccacta aaccagcctc aagaacaccc gaatggagtc tctaagctac ataataccaa 2100 cttacacttt acaaaatgtt gtcccccaaa atgtagccat tcgtatctgc tcctaataaa 2160 aagaaagttt cttcacattc taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaccccc 2220 cccccccccc ccctgcagag atctgctagc ttgagtattc tatagagtca cctaaatact 2280 &lt;210&gt; 222 &lt;211&gt; 2597 &lt;212&gt; DNA &lt;213&gt; 智人 &lt;400&gt; 222 gtgcttcccc gcccctgaac ctgctccctc ccagtcggtc tcgccgcgct cgccgggtgt 60 cccagtgtca ccaacactcg gccgccgccg ccagcttggc gcgcaccgcc gcctccgcca 120 ccgccgacag cgcgcatcct ccgtgtcccc gctccgccgc ccgagcaggt gccactatgc 180 acgtgaagaa gtacctgctg aagggcctgc atcggctgca gaagggcccc ggctacacgt 240 acaaggagct gctggtgtgg tactgcgaca acaccaacac ccacggcccc aagcgcatca 300 tctgtgaggg gcccaagaag aaagccatgt ggttcctgct caccctgctc ttcgccgccc 360 tcgtctgctg gcagtggggc atcttcatca ggacctactt gagctgggag gtcagcgtct 420 ccctctccgt aggcttcaag accatggact tccctgccgt caccatctgc aatgctagcc 480 ccttcaagta ttccaaaatc aagcatttgc tgaaggacct ggatgagctg atggaagctg 540 tcctggagag aatcctggct cctgagctaa gccatgccaa tgccaccagg aacctgaact 600 tctccatctg gaaccacaca cccctggtcc ttattgatga acggaacccc caccacccca 660 tggtccttga tctctttgga gacaaccaca atggcttaac aagcagctca gcatcagaaa 720 agatctgtaa tgcccacggg tgcaaaatgg ccatgagact atgtagcctc aacaggaccc 780 agtgtacctt ccggaacttc accagtgcta cccaggcatt gacagagtgg tacatcctgc 840 aggccaccaa catctttgca caggtgccac agcaggagct agtagagatg agctaccccg 900 • 44- 154740·序列表.doc 960 960201141489 &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 220 ugccuucucu gucaugccc &lt;210&gt; 221 &lt;211&gt; 2280 &lt;212&gt; DNA &lt;213&gt; stone crab wolf &lt;400&gt; 221 ggtacccagc ttgcttgttc tttttgcaga agctcagaat aaacgctcaa ctttggcaga tcaattcccc ggggatccga attcgccacc atgcacgtga agaagtacct gctgaagtgc ctgcaccggc tgcagaaggg ccccggctac acgtacaagg agctgctggt gtggtactgc gataacacca acacccacgg ccccaagcgt atcatctgcg aggggcccaa gaagaaagcc gtgtggttcc tgctcaccct gctcttcact gctctcgtct gctggcagtg gggcatcttc atcaggacct acttgagctg ggaggtcagc gtctccctct ccgtaggctt caagaccatg gacttccccg ccgtcaccat ctgcaatgct agccccttca agtattccaa agtcaagcat ttgctgaagg acctggatga gctgatggaa gctgtcctgg agagaatcct ggctcctgag ctaagccatg ccaatgccac caggaccctg aactcttcca tctggaacca cacaccactg gtccttattg Atgaacggaa cccccaccac cccatggtcc tcgatctctt tggagataac cacaatggct taacaaacag ctcagcatca gaaaagatct gtaatgccca tgggtgcaaa atggccatga gactatgtag cctcaacggg acccagtgca ccttccggaa cttcaccagc gctacccagg cagtgacaga gtggtacagc ctgcag gcca ccaacatctt tgcgcaggtg ccgcagcagg agctggtgga gatgagctac cccggcgagc agatgatcct ggcctgcctg tttggagctg agccctgcaa ctaccggaac ttcacgtcca tcttctaccc tcactatggc aactgttaca tcttcaactg gggcatgaca gagaaggcac ttccttcggc caaccctgga cctgaatttg gcctgaagtt gatcctggac ataggccagg aagactacgt ccccttcctc gcgtccacgg ctggggtcag gctgatgctt cacgagcaga ggtcataccc cttcatcaga gacgagggca tctatgccat gtcggggaca gagacgtcca tcggggtact cgtggacaag cttcagcgca tgggggagcc ctacagcccg tgcaccgtga atggctccga ggtccccgtc caaaacttct acagtgacta caacacgacc tactccatcc aggcctgtct tcgctcctgc ttccaagacc acatgatccg tagctgcaag tgtgggcact acctctaccc actgccccgt ggggagaaat actgcaacaa ccgggacttc ccagactggg cccattgcta ctcagatctg cagatgagcg tggcgcagag agagacctgc attggcatgt gcaaggaatc ctgcaatgac acccagtaca agatgactat ctccatggct gactggcctt ctgaggcctc tgaggactgg 154740- sequence Listing .doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 43- 1500 201141489 attttccacg tcttgtctca ggagcgggac caaag cacca atatcaccct gagcaggaag 1560 ggaattgtca agctcaacat ctacttccaa gaatttaact atcgcaccat tgaagaatca 1620 gcagccaata acctcgtctg gctgctctca aatctgggtg gccagtttgg cttctggatg 1680 gggggctctg tgctgtgcct catcgagttt ggggagatca tcatcgactt tgtgtggatc 1740 accatcatca agctggtggc cttggccaag agcctccggc agcggcgagc ccaagccagc 1800 tactccggcc caccgcccac ggtggctgag ctggtggagg cccacaccaa cttcggctac I860 cagcctgaca cggccccccg cagccccaac accgggccct accccagtga gcaggccctg 1920 cccatcccgg gcaccccgcc ccccaactat gactccctgc gtctgcagcc actggacgtc 1980 atcgagtctg acagtgaggg tgatgccatc taagcggccg cctagaaata gcttgatctg 2040 gttaccacta aaccagcctc aagaacaccc gaatggagtc tctaagctac ataataccaa 2100 cttacacttt acaaaatgtt gtcccccaaa atgtagccat tcgtatctgc tcctaataaa 2160 aagaaagttt cttcacattc taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaccccc 2220 cccccccccc ccctgcagag atctgctagc ttgagtattc tatagagtca cctaaatact 2280 &lt; 210 &gt; 222 &lt; 211 &gt; 2597 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 222 gtgcttcccc gcccctgaac ctgctccct c ccagtcggtc tcgccgcgct cgccgggtgt 60 cccagtgtca ccaacactcg gccgccgccg ccagcttggc gcgcaccgcc gcctccgcca 120 ccgccgacag cgcgcatcct ccgtgtcccc gctccgccgc ccgagcaggt gccactatgc 180 acgtgaagaa gtacctgctg aagggcctgc atcggctgca gaagggcccc ggctacacgt 240 acaaggagct gctggtgtgg tactgcgaca acaccaacac ccacggcccc aagcgcatca 300 tctgtgaggg gcccaagaag aaagccatgt ggttcctgct caccctgctc ttcgccgccc 360 tcgtctgctg gcagtggggc atcttcatca ggacctactt gagctgggag gtcagcgtct 420 ccctctccgt aggcttcaag accatggact tccctgccgt caccatctgc aatgctagcc 480 ccttcaagta ttccaaaatc aagcatttgc tgaaggacct ggatgagctg atggaagctg 540 tcctggagag aatcctggct cctgagctaa gccatgccaa tgccaccagg aacctgaact 600 tctccatctg gaaccacaca cccctggtcc ttattgatga acggaacccc caccacccca 660 tggtccttga tctctttgga gacaaccaca atggcttaac aagcagctca gcatcagaaa 720 agatctgtaa tgcccacggg tgcaaaatgg ccatgagact atgtagcctc aacaggaccc 780 agtgtacctt ccggaacttc accagtgcta cccaggcatt gacagagtgg tacatcctgc 840 aggccaccaa catctttgca caggtgccac agcaggagct Agtagaga Tg agctaccccg 900 • 44- 154740 · Sequence Listing. doc 960 960

201141489 gcgagcagat gatcctggcc tgcctattcg gagctgagcc ctgcaactac cggaacttca cgtccatctt ctaccctcac tatggcaact gttacatctt caactggggc atgacagaga aggcacttcc ttcggccaac cctggaactg aattcggcct gaagttgatc ctggacatag gccaggaaga ctacgtcccc ttccttgcgt ccacggccgg ggtcaggctg atgcttcacg agcagaggtc ataccccttc atcagagatg agggcatcta cgccatgtcg gggacagaga cgtccatcgg ggtactcgtg gacaagcttc agcgcatggg ggagccctac agcccgtgca ccgtgaatgg ttctgaggtc cccgtccaaa acttctacag tgactacaac acgacctact ccatccaggc ctgtcttcgc tcctgcttcc aagaccacat gatccgtaac tgcaactgtg gccactacct gtacccactg ccccgtgggg agaaatactg caacaaccgg gacttcccag actgggccca ttgctactca gatctacaga tgagcgtggc gcagagagag acctgcattg gcatgtgcaa ggagtcctgc aatgacaccc agtacaagat gaccatctcc atggctgact ggccttctga ggcctccgag gactggattt tccacgtctt gtctcaggag cgggaccaaa gcaccaatat caccctgagc aggaagggaa ttgtcaagct caacatctac ttccaagaat ttaactatcg caccattgaa gaatcagcag ccaataacat cgtctggctg ctctcgaatc tgggtggcca gtttggcttc tggatggggg gctctgtgct gtgcctcatc gagtttgggg agatcatcat cgactttgtg tggatcacca tcatcaagct ggtggccttg gccaagagcc tacggcagcg gcgagcccaa gccagctacg ctggcccacc gcccaccgtg gccgagctgg tggaggccca caccaacttt ggcttccagc ctgacacggc cccccgcagc cccaacactg ggccctaccc cagtgagcag gccctgccca tcccaggcac cccgcccccc aactatgact ccctgcgtct gcagccgctg gacgtcatcg agtctgacag tgagggtgat gccatctaac cctgcccctg cccaccccgg gcggctgaaa ctcactgagc agccaagact gttgcccgag gcctcactgt atggtgccct ctccaaaggg tcgggagggt agctctccag gccagagctt gtgtccttca acagagaggc cagcggcaac tggtccgtta ctggccaagg gctctgtaga atcacggtgc tggtacagga tgcaggaata aattgtatct tcacctggtt cctaccctcg tccctacctg tcctgatcct ggtcctgaag acccctcgga acaccctctc ctggtggcag gccacttccc tcccagtgcc agtctccatc caccccagag aggaacaggc gggtgggcca tgtggttttc tccttcctgg ccttggctgg cctctggggc aggggtggtg gagagatgga agggcatcag gtgtagggac cctgccaagt ggcacctgat ttactctaga aaataaaagt agaaaatact gagtcca &lt;210&gt; 223 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 154740·序列表.doc 45- 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2597 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 223 ugaagaagua cc &lt;210&gt; 224 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 224 gguacuucuu ca &lt;210&gt; 225 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 225 gaagaaguac cu &lt;210&gt; 226 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 226 agguacuucu uc &lt;210&gt; 227 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 227 aagaaguacc ug &lt;210&gt; 228 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12201141489 gcgagcagat gatcctggcc tgcctattcg gagctgagcc ctgcaactac cggaacttca cgtccatctt ctaccctcac tatggcaact gttacatctt caactggggc atgacagaga aggcacttcc ttcggccaac cctggaactg aattcggcct gaagttgatc ctggacatag gccaggaaga ctacgtcccc ttccttgcgt ccacggccgg ggtcaggctg atgcttcacg agcagaggtc ataccccttc atcagagatg agggcatcta cgccatgtcg gggacagaga cgtccatcgg ggtactcgtg gacaagcttc agcgcatggg ggagccctac agcccgtgca ccgtgaatgg ttctgaggtc cccgtccaaa acttctacag tgactacaac acgacctact ccatccaggc ctgtcttcgc tcctgcttcc aagaccacat gatccgtaac tgcaactgtg gccactacct gtacccactg ccccgtgggg agaaatactg caacaaccgg gacttcccag actgggccca ttgctactca gatctacaga tgagcgtggc gcagagagag acctgcattg gcatgtgcaa ggagtcctgc aatgacaccc agtacaagat gaccatctcc atggctgact ggccttctga ggcctccgag gactggattt tccacgtctt gtctcaggag cgggaccaaa gcaccaatat caccctgagc aggaagggaa ttgtcaagct caacatctac ttccaagaat ttaactatcg caccattgaa gaatcagcag ccaataacat cgtctggctg ctctcgaatc tgggtggcca gtttggcttc tggatggggg gctctgtgct gtgcctcatc gagtttgggg agatcatcat cgactttgtg tggatcacca tcatcaagct ggtggccttg gccaagagcc tacggcagcg gcgagcccaa gccagctacg ctggcccacc gcccaccgtg gccgagctgg tggaggccca caccaacttt ggcttccagc ctgacacggc cccccgcagc cccaacactg ggccctaccc cagtgagcag gccctgccca tcccaggcac cccgcccccc aactatgact ccctgcgtct gcagccgctg gacgtcatcg agtctgacag tgagggtgat gccatctaac cctgcccctg cccaccccgg gcggctgaaa ctcactgagc agccaagact gttgcccgag gcctcactgt atggtgccct ctccaaaggg tcgggagggt agctctccag gccagagctt gtgtccttca acagagaggc cagcggcaac tggtccgtta ctggccaagg gctctgtaga atcacggtgc tggtacagga tgcaggaata aattgtatct tcacctggtt cctaccctcg tccctacctg tcctgatcct ggtcctgaag acccctcgga acaccctctc ctggtggcag gccacttccc tcccagtgcc agtctccatc caccccagag aggaacaggc gggtgggcca tgtggttttc tccttcctgg ccttggctgg cctctggggc aggggtggtg gagagatgga agggcatcag gtgtagggac cctgccaagt ggcacctgat ttactctaga aaataaaagt agaaaatact gagtcca &lt; 210 &gt; 223 &lt; 211 &gt; 12 &lt; 212 &gt; RNA &lt; 213 &gt; artificial 154740·Listing list.doc 45- 1020 1080 1140 1200 1260 1320 1 380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2597 12201141489 &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 223 ugaagaagua cc &lt;210&gt; 224 &lt;211&gt;&lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 224 gguacuucuu ca &lt;210&gt; 225 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 225 gaagaaguac cu &lt;210&gt; 226 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 226 agguacuucu Uc &lt;210&gt; 227 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 227 aagaaguacc ug &lt;210&gt; 228 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent 12 12 12 12

154740-序列表.doc -46- 12201141489154740-Sequence List.doc -46- 12201141489

&lt;400&gt; 228 cagguacuuc uu &lt;210&gt; 229 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 229 agaaguaccu gc &lt;210&gt; 230 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 230 gcagguacuu cu &lt;210&gt; 231 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 231 gaaguaccug cu &lt;210&gt; 232 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 232 agcagguacu uc &lt;210&gt; 233 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 2B3 aaguaccugc ug 12 12 12 12 154740-序列表.doc 47 · 12 12201141489 &lt;210&gt; 234 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 234 cagcagguac uu &lt;210&gt; 235 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 235 aguaccugcu ga &lt;210&gt; 236 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 236 ucagcaggua cu &lt;210&gt; 237 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 237 guaccugcug aa &lt;210&gt; 238 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 238 uucagcaggu ac &lt;210&gt; 239 12 12 12 12&lt;400&gt; 228 cagguacuuc uu &lt;210&gt; 229 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 229 agaaguaccu gc &lt;210&gt; 230 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 230 gcagguacuu cu &lt;210&gt; 231 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 231 gaaguaccug cu &lt;210&gt; 232 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 232 agcagguacu uc &lt;210&gt; 233 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 2B3 aaguaccugc ug 12 12 12 12 154740 - Sequence Listing .doc 47 · 12 12201141489 &lt;210&gt; 234 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 234 cagcagguac uu &lt;210&gt; 235 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 235 aguaccugcu ga &lt;210&gt; 236 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 236 ucagcaggua cu &lt;210&gt;; 237 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 237 guaccugcug aa &lt;210&gt; 238 &lt;211&gt; 12 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 238 uucagcaggu ac &lt;210&gt; 239 12 12 12 12

】54740·序列表.doc -48 - 12201141489】 54740· Sequence Listing.doc -48 - 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 239 gagcugggag gu &lt;210&gt; 240 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 240 accucccagc uc &lt;210&gt; 241 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 241 agcugggagg uc &lt;210&gt; 242 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 242 gaccucccag cu &lt;210&gt; 243 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 243 gcugggaggu ca &lt;210&gt; 244 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc 49 · 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 244 ugaccuccca gc &lt;210&gt; 245 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 245 cugggagguc ag &lt;210&gt; 246 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 246 cugaccuccc ag &lt;210&gt; 247 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 247 ugggagguca gc &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 12 12 12 8 A工 4 2 N J 2 1 R Λ&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 239 gagcugggag gu &lt;210&gt; 240 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 240 accucccagc uc &lt;210&gt; 241 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;;400&gt; 241 agcugggagg uc &lt;210&gt; 242 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;4〇〇&gt; 242 gaccucccag cu &lt;210&gt; 243 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 243 gcugggaggu ca &lt;210&gt; 244 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor 12 12 12 12 154740 - Sequence Listing. doc 49 · 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 244 ugaccuccca gc &lt;210&gt; 245 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 245 cugggagguc ag &lt;210&gt; 246 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 246 cugaccuccc ag &lt;210&gt; 247 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 247 ugggagguca gc &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 12 12 12 8 A 4 2 NJ 2 1 R Λ

&lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 248 gcugaccucc ca 12 &lt;210&gt; 249 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;2 2 3&gt; RNAi 劑 •50· 154740·序列表.doc 12201141489&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 248 gcugaccucc ca 12 &lt;210&gt; 249 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;2 2 3&gt; RNAi agent • 50· 154740· Sequence Listing.doc 12201141489

&lt;400&gt; 249 gggaggucag eg &lt;210&gt; 250 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 250 cgcugaccuc cc &lt;210&gt; 251 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 251 ggaggucagc gu &lt;210&gt; 252 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 252 acgcugaccu cc &lt;210&gt; 253 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 253 gaggucagcg uc &lt;210&gt; 254 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 254 gacgcugacc uc 12 12 12 12 154740-序列表 _doc -51 - 12 12201141489 &lt;210&gt; 255 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 255 aggucagcgu cu &lt;210&gt; 256 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 256 agacgcugac cu &lt;210&gt; 257 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 257 cugcaggcca cc &lt;210&gt; 258 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 258 gguggccugc ag &lt;210&gt; 259 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 259 ugcaggccac ca &lt;210&gt; 260 12 12 12 12 154740·序列表.doc -52· 12201141489&lt;400&gt; 249 gggaggucag eg &lt;210&gt; 250 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 250 cgcugaccuc cc &lt;210&gt; 251 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 251 ggaggucagc gu &lt;210&gt; 252 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 252 acgcugaccu cc &lt;210&gt; 253 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 253 gaggucagcg uc &lt;210&gt; 254 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 254 gacgcugacc uc 12 12 12 12 154740 - Sequence Listing _doc -51 - 12 12201141489 &lt;210&gt; 255 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 255 aggucagcgu cu &lt;210&gt; 256 &lt;;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 256 agacgcugac cu &lt;210&gt; 257 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 257 cugcaggcca cc &lt;210&gt; 258 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 258 gguggccugc ag &lt;210&gt; 259 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 259 ugcaggccac ca &lt;210&gt; 260 12 12 12 12 154740 · Sequence Listing.doc -52· 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 260 ugguggccug ca &lt;210&gt; 261 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 261 gcaggccacc aa &lt;210&gt; 262 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 262 uugguggccu gc &lt;210&gt; 263 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 263 caggccacca ac &lt;210&gt; 264 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 264 guugguggcc ug &lt;21〇&gt; 265 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740·序列表.doe 53- 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 265 aggccaccaa ca &lt;210&gt; 266 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 266 uguugguggc cu &lt;210&gt; 267 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 267 ggccaccaac au &lt;210&gt; 268 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 268 auguuggugg cc &lt;210&gt; 269 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 269 gccaccaaca uc &lt;210&gt; 270 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12 154740-序列表.doc • 54- 12201141489&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 260 ugguggccug ca &lt;210&gt; 261 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 261 gcaggccacc aa &lt;210&gt; 262 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;;400&gt; 262 uugguggccu gc &lt;210&gt; 263 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 263 caggccacca ac &lt;210&gt; 264 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 264 guugguggcc ug &lt;21〇&gt; 265 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Artificial 12 12 12 12 154740 · Sequence Listing. doe 53- 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 265 aggccaccaa ca &lt;210&gt; 266 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; Artificial &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 266 uguugguggc cu &lt;210 &gt; 267 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 267 ggccaccaac au &lt;210&gt; 268 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 268 auguuggugg cc &lt;210&gt; 269 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 269 gccaccaaca uc &lt;210&gt; 270 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent 12 12 12 12 154740 - Sequence Listing. 54- 12201141489

&lt;400&gt; 270 gauguuggug gc &lt;210&gt; 271 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 271 ccaccaacau cu &lt;210&gt; 272 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 272 agauguuggu gg &lt;210&gt; 273 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 273 ggcaugacag ag &lt;210&gt; 274 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 274 cucugucaug cc &lt;210&gt; 275 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 275 gcaugacaga ga 12 12 12 12 154740·序列表.doc 55- 12 201141489 &lt;210&gt; 276 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 276 ucucugucau gc 12 &lt;210&gt; 277 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 277 caugacagag aa 12 &lt;210&gt; 278 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 278 uucucuguca ug 12 &lt;210&gt; 279 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 279 augacagaga ag 12 ο A工 2812叩人 &lt;210〉 &lt;211&gt; &lt;212&gt; &lt;213&gt; &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 280 cuucucuguc au 12 &lt;210&gt; 281 •56- 154740-序列表.doc 12201141489&lt;400&gt; 270 gauguuggug gc &lt;210&gt; 271 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 271 ccaccaacau cu &lt;210&gt; 272 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 272 agauguuggu gg &lt;210&gt; 273 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 273 ggcaugacag ag &lt;210&gt; 274 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 274 cucugucaug cc &lt;210&gt; 275 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 275 gcaugacaga ga 12 12 12 12 154740·SEQ ID .doc 55- 12 201141489 &lt;210&gt; 276 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 276 ucucugucau gc 12 &lt;210&gt; 277 &lt;;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &l t;400&gt; 277 caugacagag aa 12 &lt;210&gt; 278 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 278 uucucuguca ug 12 &lt;210&gt; 279 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 279 augacagaga ag 12 ο A worker 2812 叩人&lt;210> &lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 280 cuucucuguc au 12 &lt;210&gt; 281 • 56-154740-sequence table.doc 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 281 ugacagagaa gg &lt;210&gt; 282 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 282 ccuucucugu ca &lt;210&gt; 283 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 283 gacagagaag gc &lt;210&gt; 284 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 284 gccuucucug uc &lt;210&gt; 285 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 285 acagagaagg ca &lt;210&gt; 286 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc 57- 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 286 ugccuucucu gu &lt;210&gt; 287 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 287 cagagaaggc ac &lt;210&gt; 288 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 288 gugccuucuc ug &lt;210&gt; 289 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 289 agagaaggca cu &lt;210&gt; 290 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 290 agugccuucu cu &lt;210&gt; 291 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12 154740·序列表.doc -58 - 12201141489&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 281 ugacagagaa gg &lt;210&gt; 282 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 282 ccuucucugu ca &lt;210&gt; 283 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;220&gt;;400&gt; 283 gacagagaag gc &lt;210&gt; 284 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 284 gccuucucug uc &lt;210&gt; 285 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 285 acagagaagg ca &lt;210&gt; 286 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 12 12 12 12 154740 - Sequence Listing. doc 57- 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 286 ugccuucucu gu &lt;210&gt; 287 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 287 cagagaaggc ac &lt;210&gt ; 288 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 288 gugccuucuc ug &lt;210&gt; 289 &lt;211&gt; 12 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 289 agagaaggca cu &lt;210&gt; 290 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 290 agugccuucu cu &lt;210&gt; 291 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 12 12 12 12 154740 · Sequence Listing.doc -58 - 12201141489

&lt;400&gt; 291 gagaaggcac uu &lt;210&gt; 292 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 292 aagugccuuc uc &lt;210&gt; 293 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 293 agaaggcacu uc &lt;210&gt; 294 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 294 gaagugccuu cu &lt;210&gt; 295 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 295 gaaggcacuu cc &lt;210&gt; 296 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 296 ggaagugccu uc 12 12 12 12 154740·序列表.doc ·59· 12 12201141489 &lt;210&gt; 297 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 297 aaggcacuuc cu 8 A工 9 2 NL 2 1 R Λ &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 298 aggaagugcc uu &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 299 12 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 299 aggcacuucc uu &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;21B&gt; 300 12 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 300 aaggaagugc cu &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 301 12 RNA 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 301 cuacagugac ua &lt;210&gt; 302 12 12 12 12 】54740-序列表.doc -60- 12201141489&lt;400&gt; 291 gagaaggcac uu &lt;210&gt; 292 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 292 aagugccuuc uc &lt;210&gt; 293 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 293 agaaggcacu uc &lt;210&gt; 294 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 294 gaagugccuu cu &lt;210&gt; 295 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 295 gaaggcacuu cc &lt;210&gt; 296 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 296 ggaagugccu uc 12 12 12 12 154740·SEQ ID NO. .doc ·59· 12 12201141489 &lt;210&gt; 297 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 297 aaggcacuuc cu 8 A worker 9 2 NL 2 1 R Λ &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; RN Ai agent &lt;400&gt; 298 aggaagugcc uu &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 299 12 RNA artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 299 aggcacuucuc uu &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;21B&gt; 300 12 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 300 aaggaagugc cu &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 12 RNA Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 301 cuacagugac ua &lt;210&gt; 302 12 12 12 12 】54740 - Sequence Listing.doc -60- 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 302 uagucacugu ag &lt;210&gt; 303 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 303 uacagugacu ac &lt;210&gt; 304 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 304 guagucacug ua &lt;210&gt; 305 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 305 acagugacua ca &lt;210&gt; 306 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 306 uguagucacu gu &lt;210&gt; 307 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc •61 - 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 307 cagugacuac aa &lt;210&gt; 308 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 308 uuguagucac ug &lt;210&gt; 309 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 309 agugacuaca ac &lt;210&gt; 310 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 310 guuguaguca cu &lt;210&gt; 311 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 311 gugacuacaa ca &lt;210&gt; 312 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 302 uagucacugu ag &lt;210&gt; 303 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 303 uacagugacu ac &lt;210&gt; 304 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent&lt;220&gt;;400&gt; 304 guagucacug ua &lt;210&gt; 305 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 305 acagugacua ca &lt;210&gt; 306 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 306 uguagucacu gu &lt;210&gt; 307 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 12 12 12 12 154740 - Sequence Listing. doc • 61 - 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 307 cagugacuac aa &lt;210&gt; 308 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 308 uuguagucac ug &lt;210&Gt; 309 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 309 agugacuaca ac &lt;210&gt; 310 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 310 guuguaguca cu &lt;210&gt; 311 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 311 gugacuacaa ca &lt;210&gt; 312 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 12 12 12 12

154740·序列表.doc -62- 12201141489154740· Sequence Listing.doc -62- 12201141489

&lt;400&gt; 312 uguuguaguc ac &lt;210&gt; 313 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 313 ugacuacaac ac &lt;210&gt; 314 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 314 guguuguagu ca &lt;210&gt; 315 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇0&gt; 315 gacuacaaca eg &lt;210&gt; 316 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 316 cguguuguag uc &lt;210&gt; 317 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 317 acuacaacac ga 12 12 12 12 154740-序列表.doc 63- 12 12201141489 &lt;210&gt; 318 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 318 ucguguugua gu &lt;210&gt; 319 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 319 cuacaacacg ac &lt;210&gt; 320 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 320 gucguguugu ag &lt;210&gt; 321 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 321 uacaacacga cc &lt;210&gt; 322 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 322 ggucguguug ua &lt;210&gt; 323 12 12 12 12 154740*序列表.doc ·64· 12201141489&lt;400&gt; 312 uguuguaguc ac &lt;210&gt; 313 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 313 ugacuacaac ac &lt;210&gt; 314 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 314 guguuguagu ca &lt;210&gt; 315 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;4〇0&gt; 315 gacuacaaca eg &lt;210&gt; 316 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 316 cguguuguag uc &lt;210&gt; 317 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 317 acuacaacac ga 12 12 12 12 154740- Sequence Listing.doc 63- 12 12201141489 &lt;210&gt; 318 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 318 ucguguugua gu &lt;210&gt;&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 319 cuacaacacg ac &lt;210&gt; 320 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 320 gucguguugu ag &lt;210&gt;; 321 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 321 uacaacacga cc &lt;210&gt; 322 &lt;211&gt; 12 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 322 ggucguguug ua &lt;210&gt; 323 12 12 12 12 154740* Sequence Listing.doc ·64· 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 323 acaacacgac cu &lt;210&gt; 324 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 324 aggucguguu gu &lt;210&gt; 325 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 325 ggagaaauac ug &lt;210&gt; 326 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 326 caguauuucu cc &lt;210&gt; 327 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 327 gagaaauacu gc &lt;210&gt; 328 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc 65- 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 328 gcaguauuuc uc &lt;210&gt; 329 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 329 agaaauacug ca &lt;210&gt; 330 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 330 ugcaguauuu cu &lt;210&gt; 331 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 331 gaaauacugc aa &lt;210&gt; 332 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400〉 332 uugcaguauu uc &lt;210&gt; 333 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 323 acaacacgac cu &lt;210&gt;324 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 324 aggucguguu gu &lt;210&gt; 325 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;223&gt;;400&gt; 325 ggagaaauac ug &lt;210&gt; 326 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 326 caguauuucu cc &lt;210&gt; 327 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 327 gagaaauacu gc &lt;210&gt; 328 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 12 12 12 12 154740-Sequence Listing.doc 65- 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 328 gcaguauuuc uc &lt;210&gt; 329 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 329 agaaauacug ca &lt;210&gt 330 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 330 ugcaguauuu cu &lt;210&gt; 331 &lt;211&gt; 12 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 331 gaaauacugc aa &lt;210&gt; 332 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400> 332 uugcaguauu uc &lt;210&gt; 333 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 12 12 12 12

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&lt;400&gt; 333 aaauacugca ac &lt;210&gt; 334 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 334 guugcaguau uu &lt;210&gt; 335 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 335 aauacugcaa ca &lt;210&gt; 336 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 336 uguugcagua uu &lt;210&gt; 337 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 337 auacugcaac aa &lt;210&gt; 338 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 338 uuguugcagu au 12 12 12 12 154740-序列表.doc -67- 12 12201141489 &lt;210&gt; 339 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 339 ucuccauggc ug &lt;210&gt; 340 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 340 cagccaugga ga &lt;210&gt; 341 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 341 cuccauggcu ga &lt;210&gt; 342 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 342 ucagccaugg ag &lt;210&gt; 343 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 343 uccauggcug ac &lt;210&gt; 344 12 12 12 12 154740-序列表.doc • 68 - 12201141489&lt;400&gt; 333 aaauacugca ac &lt;210&gt; 334 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 334 guugcaguau uu &lt;210&gt; 335 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 335 aauacugcaa ca &lt;210&gt; 336 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 336 uguugcagua uu &lt;210&gt; 337 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 337 auacugcaac aa &lt;210&gt; 338 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 338 uuguugcagu au 12 12 12 12 154740 - Sequence Listing .doc -67- 12 12201141489 &lt;210&gt; 339 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 339 ucuccauggc ug &lt;210&gt; 340 &lt;;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 340 cagccaugga ga &lt;210&gt; 341 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 341 cuccauggcu ga &lt;210&gt; 342 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 342 ucagccaugg ag &lt;210&gt; 343 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 343 uccauggcug ac &lt;210&gt; 344 12 12 12 12 154740 - Sequence Listing.doc • 68 - 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; . &lt;223&gt; RNAi 劑 &lt;400&gt; 344 gucagccaug ga &lt;210&gt; 345 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 345 ccauggcuga cu &lt;210&gt; 346 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 346 agucagccau gg &lt;210&gt; 347 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 347 cauggcugac ug &lt;210&gt; 348 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 348 cagucagcca ug &lt;210&gt; 349 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc 69- 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 349 auggcugacu gg &lt;210&gt; 350 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 350 ccagucagcc au &lt;210&gt; 351 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 351 uggcugacug gc &lt;210&gt; 352 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 352 gccagucagc ca &lt;210&gt; 353 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 353 auaucacccu ga &lt;210&gt; 354 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;. &lt;223&gt; RNAi agent &lt;400&gt; 344 gucagccaug ga &lt;210&gt; 345 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 345 ccauggcuga cu &lt;210&gt; 346 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 346 agucagccau gg &lt;210&gt; 347 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 347 cauggcugac ug &lt;210&gt; 348 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 348 cagucagcca ug &lt;210&gt; 349 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Artificial 12 12 12 12 154740 - Sequence Listing. doc 69- 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 349 auggcugacu gg &lt;210&gt; 350 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 350 ccagucagcc au &lt;210&Gt; 351 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 351 uggcugacug gc &lt;210&gt; 352 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 352 gccagucagc ca &lt;210&gt; 353 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 353 auaucacccu ga &lt;210&gt; 354 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 12 12 12 12

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&lt;400&gt; 354 ucagggugau au &lt;210&gt; 355 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 355 uaucacccug ag &lt;210&gt; 356 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 356 cucaggguga ua &lt;210&gt; 357 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 357 aucacccuga gc &lt;210&gt; 358 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 358 gcucagggug au &lt;210&gt; 359 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400 359 ucacccugag ca 12 12 12 12 154740-序列表.doc •71 · 12 12201141489 &lt;210&gt; 360 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 360 ugcucagggu ga &lt;210&gt; 361 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 361 cacccugagc ag &lt;210&gt; 362 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22Β&gt; RNAi 劑 &lt;400&gt; 362 cugcucaggg ug &lt;210&gt; 363 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 363 acccugagca gg &lt;210&gt; 364 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 364 ccugcucagg gu &lt;210&gt; 365 12 12 12 12&lt;400&gt; 354 ucagggugau au &lt;210&gt; 355 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 355 uaucacccug ag &lt;210&gt; 356 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 356 cucaggguga ua &lt;210&gt; 357 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 357 aucacccuga gc &lt;210&gt; 358 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 358 gcucagggug au &lt;210&gt; 359 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400 359 ucacccugag ca 12 12 12 12 154740 - Sequence Listing. Doc •71 · 12 12201141489 &lt;210&gt; 360 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 360 ugcucagggu ga &lt;210&gt; 361 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 361 cacccugagc ag &lt;210&gt; 362 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;22Β&gt; RNAi agent &lt;400&gt; 362 cugcucaggg ug &lt;210&gt; 363 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 363 acccugagca gg &lt;210&gt; 364 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 364 ccugcucagg gu &lt;210&gt; 365 12 12 12 12

154740-序列表.doc ·72· 12201141489154740-Sequence List.doc ·72· 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 365 cccugagcag ga &lt;210〉 366 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 366 uccugcucag gg &lt;210&gt; 367 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 367 ccugagcagg aa &lt;210&gt; 368 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 368 uuccugcuca gg &lt;210&gt; 369 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt;, 369 cugagcagga ag &lt;210&gt; 370 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc 73- 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 370 cuuccugcuc ag 12 &lt;210&gt; 371 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 371 ugagcaggaa gg 12 &lt;210&gt; 372 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 372 ccuuccugcu ca 12 &lt;210&gt; 373 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 373 uggguggcca gu 12 4 A工 72N、 3 1 R / &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 374 acuggccacc ca 12 &lt;210&gt; 375 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 -74- 154740-序列表.doc 201141489 &lt;400&gt; 375 ggguggccag uu 12 &lt;210&gt; 376 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 376 aacuggccac cc 12 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 7 A工 72 N」 31 R / &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 377 gguggccagu uu 12 &lt;210&gt; 378 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; B78 aaacuggcca cc &lt;210&gt; 379 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 379 guggccaguu ug &lt;210&gt; 380 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 380 caaacuggcc ac 12 12 154740·序列表.doc •75- 12 12201141489 &lt;210&gt; 381 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 381 uggccaguuu gg &lt;210&gt; 382 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22Β&gt; RNAi 劑 &lt;400&gt; 382 ccaaacuggc ca &lt;210&gt; 383 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 383 ggccaguuug gc &lt;210&gt; 384 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 384 gccaaacugg cc &lt;210&gt; 385 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 385 gccaguuugg cu &lt;210&gt; 386 12 12 12 12 154740·序列表.doc ·76· 12201141489 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 386 agccaaacug gc &lt;210&gt; 387 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 387 ccaguuuggc uu &lt;210&gt; 388 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 388 aagccaaacu gg &lt;210&gt; 389 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;40〇&gt; 389 caguuuggcu uc &lt;210&gt; 390 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 390 gaagccaaac ug &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 12 12 12 12 1 A工 9 2 N J 3 1 R Λ 154740-序列表.doc 77- 201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 391 1 aguuuggcuu cu 12 &lt;210&gt; 392 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 392 agaagccaaa cu 12 &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt; 3 A工 9 2 N J 3 1 R Λ &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 393 guuuggcuuc ug 12 &lt;210&gt; 394 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 394 cagaagccaa ac 12 &lt;210&gt; 395 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;22 3&gt; RNAi 劑 &lt;400&gt; 395 uuuggcuucu gg 12 &lt;210&gt; 396 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 154740-序列表.doc ·78· 12201141489&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 365 cccugagcag ga &lt;210> 366 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 366 uccugcucag gg &lt;210&gt; 367 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;;400&gt; 367 ccugagcagg aa &lt;210&gt; 368 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 368 uuccugcuca gg &lt;210&gt; 369 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt;, 369 cugagcagga ag &lt;210&gt; 370 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Artificial 12 12 12 12 154740 - Sequence Listing. doc 73-201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 370 cuuccugcuc ag 12 &lt;210&gt; 371 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 371 ugagcaggaa gg 12 &lt;210&gt; 372 &l t; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 372 ccuuccugcu ca 12 &lt;210&gt; 373 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 373 uggguggcca gu 12 4 A worker 72N, 3 1 R / &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 374 acuggccacc ca 12 &lt;210&gt; 375 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent-74-154740-preface List .doc 201141489 &lt;400&gt; 375 ggguggccag uu 12 &lt;210&gt; 376 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;4〇〇&gt; Aacuggccac cc 12 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 7 A worker 72 N" 31 R / &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 377 gguggccagu uu 12 &lt;210&gt; 378 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; B78 aaacuggcca cc &lt;210&gt; 379 &lt;211&gt; 12 &lt;212&Gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 379 guggccaguu ug &lt;210&gt; 380 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;;223&gt; RNAi agent &lt;400&gt; 380 caaacuggcc ac 12 12 154740·SEQ ID list.doc •75- 12 12201141489 &lt;210&gt; 381 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;;223&gt; RNAi agent &lt;400&gt; 381 uggccaguuu gg &lt;210&gt; 382 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;22Β&gt; RNAi agent &lt;400&gt; 382 ccaaacuggc ca &lt;;210&gt; 383 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 383 ggccaguuug gc &lt;210&gt; 384 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 384 gccaaacugg cc &lt;210&gt; 385 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 385 gccaguuugg cu &lt;210&gt; 386 12 12 12 12 1547 40· Sequence Listing.doc ·76· 12201141489 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 386 agccaaacug gc &lt;210&gt; 387 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 387 ccaguuuggc uu &lt;210&gt; 388 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 388 aagccaaacu gg &lt;210&gt; 389 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;40〇 &gt; 389 caguuuggcu uc &lt;210&gt; 390 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 390 gaagccaaac ug &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 12 12 12 12 1 A 9 2 NJ 3 1 R Λ 154740 - Sequence Listing. doc 77- 201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 391 1 aguuuggcuu cu 12 &lt;210&gt; 392 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;40 0&gt; 392 agaagccaaa cu 12 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 3 A worker 9 2 NJ 3 1 R Λ &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 393 guuuggcuuc ug 12 &lt;210&gt; 394 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 394 cagaagccaa ac 12 &lt;210&gt; 395 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 395 uuuggcuucu gg 12 &lt;210&gt; 396 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;;&lt;223&gt; RNAi Agent 154740 - Sequence Listing.doc ·78· 12201141489

&lt;400&gt; 396 ccagaagcca aa &lt;210〉 397 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 397 uuggcuucug ga &lt;210&gt; 398 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;4〇〇&gt; 398 uccagaagcc aa &lt;210&gt; 399 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 399 uggcuucugg au &lt;210&gt; 400 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 400 auccagaagc ca &lt;210&gt; 401 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 401 ggcuucugga ug 12 12 12 12 154740-序列表.doc 79- 12 12201141489 &lt;210&gt; 402 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 402 cauccagaag cc &lt;210&gt; 403 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 403 gcuucuggau gg &lt;210&gt; 404 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 404 ccauccagaa gc &lt;210&gt; 405 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 405 agcuggugga gg &lt;210&gt; 406 &lt;211&gt; 12 &lt;212&gt; RNA &lt;21Β&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 406 ccuccaccag cu &lt;210&gt; 407 12 12 12 12 154740·序列表.doc ·80· 12201141489&lt;400&gt; 396 ccagaagcca aa &lt;210> 397 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 397 uuggcuucug ga &lt;210&gt; 398 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;4〇〇&gt; 398 uccagaagcc aa &lt;210&gt; 399 &lt;211&gt; 12 &lt;212&gt; RNA &lt;;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 399 uggcuucugg au &lt;210&gt; 400 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi </ RTI> &lt - Sequence Listing. doc 79- 12 12201141489 &lt;210&gt; 402 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 402 cauccagaag cc &lt;210&gt; 403 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 403 gcuucuggau gg &lt;210&gt; 404 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 404 ccauccagaa gc &lt;210&gt; 405 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 405 agcuggugga gg &lt;210&gt; 406 &lt;211&gt; 12 &lt;212&gt; RNA &lt;21Β&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 406 ccuccaccag cu &lt;210&gt; 407 12 12 12 12 154740·SEQ ID NO. doc ·80· 12201141489

&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 407 gcugguggag gc &lt;210&gt; 408 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 408 gccuccacca gc &lt;210&gt; 409 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 409 cugguggagg cc &lt;210&gt; 410 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 410 ggccuccacc ag &lt;210&gt; 411 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 411 ugguggaggc cc &lt;210&gt; 412 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 12 12 12 12 154740-序列表.doc -81 _ 12201141489 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 412 gggccuccac ca &lt;210&gt; 413 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 413 gguggaggcc ca &lt;210&gt; 414 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 414 ugggccucca cc &lt;210&gt; 415 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 415 guggaggccc ac &lt;210&gt; 416 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 416 gugggccucc ac &lt;210&gt; 417 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 12 12 12 12 154740-序列表.doc -82- 12201141489&lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 407 gcugguggag gc &lt;210&gt; 408 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;; artificial &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 408 gccuccacca gc &lt;210&gt; 409 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;;400&gt; 409 cugguggagg cc &lt;210&gt; 410 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 410 ggccuccacc ag &lt;210&gt; 411 &lt; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 411 ugguggaggc cc &lt;210&gt; 412 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 12 12 12 12 154740 - Sequence Listing. doc -81 _ 12201141489 &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 412 gggccuccac ca &lt;210&gt; 413 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 413 gguggaggcc ca &lt;210&Gt; 414 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 414 ugggccucca cc &lt;210&gt; 415 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 415 guggaggccc ac &lt;210&gt; 416 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi &lt;400&gt; 416 gugggccucc ac &lt;210&gt; 417 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent 12 12 12 12 154740 - Sequence Listing.doc - 82- 12201141489

&lt;400&gt; 417 uggaggccca ca &lt;210&gt; 418 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 418 ugugggccuc ca &lt;210&gt; 419 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 419 ggaggcccac ac &lt;210&gt; 420 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 420 gugugggccu cc &lt;210&gt; 421 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 421 gaggcccaca cc &lt;210&gt; 422 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 422 ggugugggcc uc 12 12 12 12 154740·序列表.doc -83 - 12 12201141489 &lt;210&gt; 423 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 423 aggcccacac ca &lt;210&gt; 424 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 424 uggugugggc cu &lt;210&gt; 425 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 425 ggcccacacc aa &lt;210&gt; 426 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 426 uugguguggg cc &lt;210&gt; 427 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400〉 427 gcccacacca ac &lt;210&gt; 428 12 12 12 12 154740·序列表.doc -84- 201141489 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;22〇&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 428 guuggugugg gc .12 &lt;210&gt; 429 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223》 RNAi 劑 &lt;400&gt; 429 cagugacuac aacacgacc 19&lt;400&gt; 417 uggaggccca ca &lt;210&gt; 418 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 418 ugugggccuc ca &lt;210&gt; 419 &lt;; 211 &gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 419 ggaggcccac ac &lt;210&gt; 420 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 420 gugugggccu cc &lt;210&gt; 421 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent&lt;400&gt; 421 gaggcccaca cc &lt;210&gt; 422 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 422 ggugugggcc uc 12 12 12 12 154740·SEQ ID .doc -83 - 12 12201141489 &lt;210&gt; 423 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 423 aggcccacac ca &lt;210&gt; 424 &lt;;211&gt; 12 &lt;212&gt; RNA &lt;213&gt;Labor&lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 424 uggugugggc cu &lt;210&gt; 425 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 425 ggcccacacc aa &lt;210&gt; 426 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 426 uugguguggg cc &lt;210&gt; 427 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400> 427 gcccacacca ac &lt;210&gt; 428 12 12 12 12 154740 · Sequence Listing. doc -84 - 201141489 &lt;211&gt; 12 &lt;212&gt; RNA &lt;213&gt; Labor &lt;22〇&gt;&lt;223&gt; RNAi Agent &lt;400&gt; 428 guuggugugg gc .12 &lt;210&gt; 429 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;;&lt;223&gt; RNAi agent &lt;400&gt; 429 cagugacuac aacacgacc 19

&lt;210&gt; 430 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; 人工 &lt;220&gt; &lt;223&gt; RNAi 劑 &lt;400&gt; 430 19 -85- ggucguguug uagucacug 154740-序列表.doc&lt;210&gt; 430 &lt;211&gt; 19 &lt;212&gt; RNA &lt;213&gt; Labor &lt;220&gt;&lt;223&gt; RNAi agent &lt;400&gt; 430 19 -85- ggucguguug uagucacug 154740 - Sequence Listing.doc

Claims (1)

201141489 七、申請專利範圍： 1. 一種包含RNAi劑之組合物，該RNAi劑包含有義股及反 義股’其中該反義股包含至少15個連續（contiguous)核苦 酸有〇、1、2或3個核苷酸不同於對表1中提供之β-ENaC 具有特異性之RNAi劑之反義股。 2·如請求項1之組合物’其中該組合物另外包含針對β_ ENaC之第：RNAi劑。201141489 VII. Patent Application Range: 1. A composition comprising an RNAi agent comprising a sense strand and an antisense strand wherein the antisense strand comprises at least 15 contiguous nucleotides, Two or three nucleotides differ from the antisense strand of the RNAi agent specific for the β-ENaC provided in Table 1. 2. The composition of claim 1 wherein the composition additionally comprises a: RNAi agent for β_ENaC. 3. 如請求項1之組合物，其中該RNAi劑包含至少一個經修 飾骨架及/或至少一個2·-經修飾核苷酸。 4. 如請求項1之組合物，其中該RNAi劑接合至一或多種選 自以下之劑：診斷化合物、報導基團、交聯劑、賦予核 酸酶抗性之部分、天然或非尋常核苷鹼基（unusual nucleobase)、親脂性分子、膽固醇、脂質、植物凝集素 (lectin)、類固醇、烏蘇醇（uva〇i)、龍舌蘭皂皆元 (hecigenin)、薯蕷息苷元（diosgenin)、萜類、三莊、较 葜皂苷元（sarsasapogenin)、無羈萜（Friedelin)、表木栓 醇（epifriedelanol)衍生之石膽酸、維生素、碳水化合 物、聚葡萄糖、普魯蘭（pullulan)、甲殼素、聚葡萄胺 糖、合成碳水化合物、寡乳酸酯15-聚合體（15-mer)、天 然聚合物、低或中分子量聚合物、菊糖（inulin)、環糊 精、玻尿酸、蛋白質、蛋白質結合劑、靶向整合素之分 子、聚陽離子、肽、多元胺、肽模擬物及/或運鐵蛋白。 5. 一種包含RNAi劑之組合物，該RNAi劑包含第一股及第 二股，其中該第一股及該第二股包含至少15個連續核苷 154740.doc 201141489 酸有0、1、2或3個核苷酸分別不同於對表！中提供之卜 ENaC具有特異性之RNAi劑之第一股及第二股。 6·如請求項1之組合物，其中該組合物包含針對p_ENaC之 第 一-RNAi劑。 7.如請求項1之組合物，其中該尺1^^劑包含硫代磷酸酯及/ 或2'-經修飾核苷酸。 8·如請求項1之組合物，其中該RNAi劑接合至—或多種 劑’該劑選自：診斷化合物、報導基團、交聯劑、賦予 核酸酶抗性之部分、天然或非尋常核苷鹼基、親脂性分 子、膽固醇、脂質、植物凝集素、類固醇、烏蘇醇、龍 舌蘭皂苷元、薯蕷皂苷元、萜類、三萜、菝葜皂苷元、 無羈萜、表木栓醇衍生之石膽酸、維生素、碳水化合 物、聚葡萄糖、普魯蘭、曱殼素、聚葡萄胺糖、合成碳 水化合物、寡乳酸酯15-聚合體、天然聚合物、低或中分 子量聚合物、菊糖、環糊精、玻尿酸、蛋白質、蛋白質 結合劑、靶向整合素之分子、聚陽離子、肽、多元胺、 肽模擬物及/或運鐵蛋白。 9. 一種包含RNAi劑之組合物的用途，該RNAi劑包含有義 k及反義股’該組合物用於製造用以治療個體之p_ENac 相關疾病的藥物，其中該反義股包含至少15個連續核苦 酸有0、1、2或3個核苷酸不同於對表1中提供之p_ENaC 具有特異性之RNAi劑之反義股。 1〇·如請求項9之用途，其中該β-ENaC相關疾病為囊腫性纖 維化、1型假醛固酮過少症（PHA1)、李德爾症候群 154740.doc 201141489 (Liddle's syndrome)、高血壓、鹼中毒、低鉀血症及/或 肥胖相關之高血壓。 11. 如請求項9之用途’其中該p_ENac相關疾病為囊腫性纖 維化、1型假醛固酮過少症（PHA1 )、李德爾症候群、高 血壓、鹼中毒、低鉀血症及/或肥胖相關之高血壓。 12. 如請求項11之用途’其中該藥物另外包含針對β_ΕΝ&amp;(：之 其他RNAi劑。 Φ 13. 一種包含RNAi劑之組合物的用途，該RNAi劑包含有義 股及反義股，該組合物用於製造用以抑制個體中之β_ ENaC基因表現的藥物，其中該反義股包含至少15個連續 核苷酸有0、1、2或3個核苷酸不同於對表丨中提供之卜 ENaC具有特異性之RNAi劑之反義股。 14. 如請求項13之用途’其中抑制該|3_ENaC基因表現係治療 β-ENaC相關疾病’該疾病為囊腫性纖維化、1型假酸固 鲷過少症（PHA1)、李德爾症候群、高血壓、鹼中毒、低 • 鉀血症及/或肥胖相關之高血壓。 15. —種藥物，其用於包含RNAi劑之RNAi調配物中，該 RNAi劑包含有義股及反義股，其中該反義股包含至少15 個連續核苷酸有〇、1、2或3個核苷酸不同於對表1中提 供之β-ENaC具有特異性之RNAi劑之反義股。 16. 如請求項丨至8中任一項之組合物’其於醫藥學上有效之 調配物中。 17·如請求項1之組合物，其用於治療個體之β-ENaC相關疾 病的方法中，該方法包含向該個體投與治療有效量之如 I54740.doc 201141489 請求項1之組合物的步驟。 18.如請求項〗至8中任—項之組合物，其用於製造用以治療 β-ENaC相關疾病之藥物。 19·如5奢求項1之組合物，其中所有嘧啶為2Ό-甲基修飾之核 苷酸。 20.如吻求項5之組合物其中所有嘧啶為2,〇_甲基修 苷酸。 '^孩 154740.doc3. The composition of claim 1, wherein the RNAi agent comprises at least one modified backbone and/or at least one 2·-modified nucleotide. 4. The composition of claim 1, wherein the RNAi agent is conjugated to one or more agents selected from the group consisting of diagnostic compounds, reporter groups, crosslinkers, nuclease-resistant portions, natural or unusual nucleosides Unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uva〇i, hecigenin, diosgenin , steroids, shuangzhuang, sarsasapogenin, sputum (Friedelin), epifriedelanol derived lithocholic acid, vitamins, carbohydrates, polydextrose, pullulan, Chitin, polyglucamine, synthetic carbohydrates, oligolactone 15-polymer (15-mer), natural polymers, low or medium molecular weight polymers, inulin, cyclodextrin, hyaluronic acid, protein , protein binding agents, molecules that target integrins, polycations, peptides, polyamines, peptidomimetics, and/or transferrin. 5. A composition comprising an RNAi agent, the RNAi agent comprising a first strand and a second strand, wherein the first strand and the second strand comprise at least 15 consecutive nucleosides 154740.doc 201141489 acid has 0, 1, 2 Or 3 nucleotides are different from the pair table! The first and second strands of RNAi agents specific to ENaC are provided. 6. The composition of claim 1 wherein the composition comprises a first-RNAi agent for p_ENaC. 7. The composition of claim 1, wherein the sizing agent comprises a phosphorothioate and/or a 2'-modified nucleotide. 8. The composition of claim 1, wherein the RNAi agent is conjugated to - or a plurality of agents selected from the group consisting of: diagnostic compounds, reporter groups, crosslinkers, nuclease-resistant portions, natural or unusual nuclei Glycosyl, lipophilic, cholesterol, lipid, phytohemagglutinin, steroid, ursolic, agave saponin, diosgenin, anthraquinone, triterpenoid, saponin, innocent, sap Alcohol-derived lithocholic acid, vitamins, carbohydrates, polydextrose, pullulan, chitin, polyglucosamine, synthetic carbohydrates, oligolactone 15-polymer, natural polymer, low or medium molecular weight polymerization , inulin, cyclodextrin, hyaluronic acid, protein, protein binder, molecules that target integrins, polycations, peptides, polyamines, peptidomimetics, and/or transferrin. 9. Use of a composition comprising an RNAi agent comprising a sense k and an antisense strand for use in the manufacture of a medicament for treating a p_ENac related disorder in an individual, wherein the antisense strand comprises at least 15 The continuous nucleotide acid has an antisense strand of 0, 1, 2 or 3 nucleotides different from the RNAi agent specific for p_ENaC provided in Table 1. 1) The use of claim 9, wherein the β-ENaC-related disease is cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome 154740.doc 201141489 (Liddle's syndrome), hypertension, alkalosis Hyperkalemia and/or obesity-related hypertension. 11. The use of claim 9 wherein the p_ENac related disease is cystic fibrosis, type 1 pseudoaldosterone deficiency (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia and/or obesity hypertension. 12. The use of claim 11 wherein the drug additionally comprises an agent for β_ΕΝ&amp; (:: other RNAi agent. Φ 13. Use of a composition comprising an RNAi agent comprising a sense share and an antisense strand, The composition is for use in the manufacture of a medicament for inhibiting the expression of the β_ENaC gene in an individual, wherein the antisense strand comprises at least 15 contiguous nucleotides having 0, 1, 2 or 3 nucleotides different from those provided in the expression ENaC has an antisense strand of a specific RNAi agent. 14. The use of claim 13 wherein the inhibition of the |3_ENaC gene expression is in the treatment of β-ENaC-related diseases. The disease is cystic fibrosis, type 1 pseudo-acid Hypertension (PHA1), lider syndrome, hypertension, alkalosis, hypokalemia, and/or obesity-related hypertension. 15. A drug used in RNAi formulations containing RNAi agents, The RNAi agent comprises a sense strand and an antisense strand, wherein the antisense strand comprises at least 15 contiguous nucleotides having 〇, 1, 2 or 3 nucleotides different from the β-ENaC provided in Table 1 Antisense stocks of sexual RNAi agents. 16. Groups from claim 丨 to 8 The composition of claim 1, wherein the composition of claim 1 is for use in a method for treating a β-ENaC-related disease in a subject, the method comprising administering to the individual a therapeutically effective amount The method of claim 1, wherein the composition of claim 1 to claim 8 is used for the manufacture of a medicament for treating a β-ENaC-related disease. The composition of claim 1, wherein all pyrimidines are 2-indolyl-methyl modified nucleotides. 20. Compositions such as Kiss 5 wherein all pyrimidines are 2, 〇-methyl succinic acid. '^孩154740. Doc
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